U.S. patent application number 11/807333 was filed with the patent office on 2008-05-29 for synthesis of triazole compounds that modulate hsp90 activity.
Invention is credited to Junghyun Chae, Dinesh U. Chimmanamada, David James, Chi-Wan Lee, Teresa Przewloka, Weiwen Ying, Shijie Zhang.
Application Number | 20080125587 11/807333 |
Document ID | / |
Family ID | 38683493 |
Filed Date | 2008-05-29 |
United States Patent
Application |
20080125587 |
Kind Code |
A1 |
Chimmanamada; Dinesh U. ; et
al. |
May 29, 2008 |
Synthesis of triazole compounds that modulate HSP90 activity
Abstract
The present invention provides novel methods of preparing
triazole compounds which inhibit the activity of Hsp90. One
embodiment of the invention is directed to methods for preparing a
triazole compound represented by the following Structural Formula:
##STR00001## or a tautomer, a pharmaceutically acceptable salt,
solvate, or clathrate, or a prodrug thereof, comprising the steps
of: a) reacting an amide represented by the following Structural
Formula: ##STR00002## with a thionation reagent to form a
thioamide; b) reacting the thioamide of step a) with hydrazine to
form a hydrazonamide; c) reacting the hydrazonamide of step b) with
a carbonylation or a thiocarbonylation reagent. In one embodiment,
the present invention is a method of synthesis of a compound of
formula (IA) ##STR00003## or a tautomer, a pharmaceutically
acceptable salt, solvate, or clathrate, or a prodrug thereof,
comprising reacting a compound of formula (IIA) ##STR00004## with
an oxidizing agent, thereby producing a compound of formula (IA).
The present invention is also directed to a method of preparing a
compound or a tautomer thereof represented by the following
Structural Formula: ##STR00005## or a tautomer, a pharmaceutically
acceptable salt, solvate, or clathrate, or a prodrug thereof. The
method comprises the step of reacting a first starting compound
represented by the following Structural Formula: ##STR00006## in
the presence of a mercuric salt, with a second starting compound
represented by the following Structural Formula: ##STR00007##
Inventors: |
Chimmanamada; Dinesh U.;
(Arlington, MA) ; Lee; Chi-Wan; (Grafton, MA)
; James; David; (Cambridge, MA) ; Zhang;
Shijie; (Nashua, NH) ; Ying; Weiwen; (Ayer,
MA) ; Chae; Junghyun; (Youngdengpo-gu, KR) ;
Przewloka; Teresa; (Tewksbury, MA) |
Correspondence
Address: |
HAMILTON, BROOK, SMITH & REYNOLDS, P.C.
530 VIRGINIA ROAD, P.O. BOX 9133
CONCORD
MA
01742-9133
US
|
Family ID: |
38683493 |
Appl. No.: |
11/807333 |
Filed: |
May 25, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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60808342 |
May 25, 2006 |
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60808376 |
May 25, 2006 |
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60808375 |
May 25, 2006 |
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60902031 |
Feb 16, 2007 |
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Current U.S.
Class: |
544/105 ;
544/132; 544/277; 546/143; 546/167; 546/272.4; 548/178; 548/217;
548/253; 548/263.2 |
Current CPC
Class: |
C07D 249/12 20130101;
C07D 401/10 20130101; C07D 413/04 20130101; C07D 403/04 20130101;
C07D 403/10 20130101; C07D 417/04 20130101; C07D 401/04 20130101;
C07D 249/14 20130101 |
Class at
Publication: |
544/105 ;
548/263.2; 546/167; 546/272.4; 546/143; 548/253; 548/178; 544/277;
544/132; 548/217 |
International
Class: |
C07D 249/12 20060101
C07D249/12; C07D 407/02 20060101 C07D407/02; C07D 403/02 20060101
C07D403/02; C07D 401/02 20060101 C07D401/02; C07D 401/04 20060101
C07D401/04; C07D 403/10 20060101 C07D403/10; C07D 417/02 20060101
C07D417/02; C07D 487/04 20060101 C07D487/04; C07D 413/12 20060101
C07D413/12; C07D 413/02 20060101 C07D413/02 |
Claims
1. A method of preparing a triazole compound represented by the
following Structural Formula: ##STR00697## or a tautomer, a
pharmaceutically acceptable salt, a solvate, a clathrate, or a
prodrug thereof, comprising the steps of: a) reacting an amide
represented by the following Structural Formula: ##STR00698## with
a thionation reagent to form a thioamide represented by the
following Structural Formula: ##STR00699## b) reacting the
thioamide of step a) with hydrazine to form a hydrazonamide
represented by the following Structural Formula: ##STR00700## c)
reacting the hydrazonamide of step b) with a carbonylation, a
thiocarbonylation reagent; or a compound of structural formula
R.sub.7N.dbd.C(X).sub.2 wherein: R.sub.1 is --OH, --SH or
--NHR.sub.7; ring A is an aryl or a heteroaryl optionally further
substituted with one or more substituents in addition to R.sub.3;
R.sub.3 is --OR.sub.26, --SR.sub.26, --O(CH.sub.2).sub.mOR.sub.A,
--O(CH.sub.2).sub.mSR.sub.B, --O(CH.sub.2).sub.mNR.sub.7R.sub.C,
--S(CH.sub.2).sub.mOR.sub.A, --S(CH.sub.2).sub.mSR.sub.B,
--S(CH.sub.2).sub.mNR.sub.7R.sub.C, --OS(O).sub.pR.sub.7,
--SS(O).sub.pR.sub.7, --S(O).sub.pOR.sub.7,
--NR.sub.7S(O).sub.pR.sub.7, --OS(O).sub.pNR.sub.10R.sub.11,
--SS(O).sub.pNR.sub.10R.sub.11,
--NR.sub.7S(O).sub.pNR.sub.10R.sub.11, --SS(O).sub.pOR.sub.7,
--NR.sub.7S(O).sub.pOR.sub.7, --OC(S)OR.sub.7, --SC(S)OR.sub.7,
--NR.sub.7C(S)OR.sub.7, --OC(S)NR.sub.10R.sub.11,
--SC(S)NR.sub.10R.sub.11, --NR.sub.7C(S)NR.sub.10R.sub.11,
--OC(NR.sub.8)R.sub.7, --SC(NR.sub.8)R.sub.7,
--NR.sub.7C(NR.sub.8)R.sub.7, --OC(NR.sub.8)OR.sub.7,
--SC(NR.sub.8)OR.sub.7, --NR.sub.7C(NR.sub.8)OR.sub.7,
--OC(NR.sub.8)NR.sub.10R.sub.11, --SC(NR.sub.8)NR.sub.10R.sub.11,
--NR.sub.7C(NR.sub.8)NR.sub.10R.sub.11, --OP(O)(OR.sub.7).sub.2, or
--SP(O)(OR.sub.7).sub.2, --OR.sub.A, --SR.sub.B, --NR.sub.7R.sub.C,
--NR.sub.26R.sub.C, or --N(R.sub.C).sub.2, wherein R.sub.A is a
hydroxyl protecting group; R.sub.B is a thiol protecting group,
R.sub.C, for each occurrence, is H or an amine protecting group,
provided at least one R.sub.C is an amine protecting group; R.sub.5
is an optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, a substituted alkyl, a substituted phenyl, an
optionally substituted heteroaryl, or an optionally substituted 8
to 14 membered aryl; R.sub.7 and R.sub.8, for each occurrence, are,
independently, --H, an optionally substituted alkyl, an optionally
substituted alkenyl, an optionally substituted alkynyl, an
optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted heterocyclyl, an optionally
substituted aryl, an optionally substituted heteroaryl, an
optionally substituted aralkyl, or an optionally substituted
heteraralkyl; R.sub.10 and R.sub.11, for each occurrence, are
independently --H, an optionally substituted alkyl, an optionally
substituted alkenyl, an optionally substituted alkynyl, an
optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted heterocyclyl, an optionally
substituted aryl, an optionally substituted heteroaryl, an
optionally substituted aralkyl, or an optionally substituted
heteraralkyl; or R.sub.10 and R.sub.11, taken together with the
nitrogen to which they are attached, form an optionally substituted
heterocyclyl or an optionally substituted heteroaryl; R.sub.26 is a
C.sub.1-C.sub.6 alkyl; p, for each occurrence, is, independently,
0, 1 or 2; m, for each occurrence, is independently, 1, 2, 3, or 4;
and X is a leaving group.
2.-3. (canceled)
4. A method of preparing a thioamide represented by the following
Structural Formula: ##STR00701## comprising the step of reacting in
a reaction mixture an amide represented by the following Structural
Formula: ##STR00702## with a thionation reagent, wherein: ring A is
an aryl or a heteroaryl optionally substituted with one or more
substituents in addition to R.sub.3; R.sub.3 is --OR.sub.26,
--SR.sub.26, --O(CH.sub.2).sub.mOR.sub.A,
--O(CH.sub.2).sub.mSR.sub.B, --O(CH.sub.2).sub.mNR.sub.7R.sub.C,
S(CH.sub.2).sub.mOR.sub.A, --S(CH.sub.2).sub.mSR.sub.B,
S(CH.sub.2).sub.mNR.sub.7R.sub.C, --OS(O).sub.pR.sub.7,
--SS(O).sub.pR.sub.7, --S(O).sub.pOR.sub.7,
--NR.sub.7S(O).sub.pR.sub.7, --OS(O).sub.pNR.sub.10R.sub.11,
--SS(O).sub.pNR.sub.10R.sub.11,
--NR.sub.7S(O).sub.pNR.sub.10R.sub.11, --SS(O).sub.pOR.sub.7,
--NR.sub.7S(O).sub.pOR.sub.7, --OC(S)OR.sub.7, --SC(S)OR.sub.7,
--NR.sub.7C(S)OR.sub.7, --OC(S)NR.sub.10R.sub.11,
--SC(S)NR.sub.10R.sub.11, --NR.sub.7C(S)NR.sub.10R.sub.11,
--OC(NR.sub.8)R.sub.7, --SC(NR.sub.8)R.sub.7,
--NR.sub.7C(NR.sub.8)R.sub.7, --OC(NR.sub.8)OR.sub.7,
--SC(NR.sub.8)OR.sub.7, --NR.sub.7C(NR.sub.8)OR.sub.7,
--OC(NR.sub.8)NR.sub.10R.sub.11, --SC(NR.sub.8)NR.sub.10R.sub.11,
--NR.sub.7C(NR.sub.8)NR.sub.10R.sub.11, --OP(O)(OR.sub.7).sub.2, or
--SP(O)(OR.sub.7).sub.2, --OR.sub.A, --SR.sub.B, --NR.sub.7R.sub.C,
--NR.sub.26R.sub.C, or --N(R.sub.C).sub.2, wherein R.sub.A is a
hydroxyl protecting group; R.sub.B is a thiol protecting group,
R.sub.C, for each occurrence, is H or an amine protecting group,
provided at least one R.sub.C is an amine protecting group; R.sub.5
is an optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, a substituted alkyl, a substituted phenyl, an
optionally substituted heteroaryl, or an optionally substituted 8
to 14 membered aryl; R.sub.7 and R.sub.8, for each occurrence, are,
independently, --H, an optionally substituted alkyl, an optionally
substituted alkenyl, an optionally substituted alkynyl, an
optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted heterocyclyl, an optionally
substituted aryl, an optionally substituted heteroaryl, an
optionally substituted aralkyl, or an optionally substituted
heteraralkyl; R.sub.10 and R.sub.11, for each occurrence, are
independently --H, an optionally substituted alkyl, an optionally
substituted alkenyl, an optionally substituted alkynyl, an
optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted heterocyclyl, an optionally
substituted aryl, an optionally substituted heteroaryl, an
optionally substituted aralkyl, or an optionally substituted
heteraralkyl; or R.sub.10 and R.sub.11, taken together with the
nitrogen to which they are attached, form an optionally substituted
heterocyclyl or an optionally substituted heteroaryl; R.sub.26 is a
C.sub.1-C.sub.6 alkyl; p, for each occurrence, is, independently,
0, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3,
or 4.
5.-7. (canceled)
8. A method of preparing a hydrazonamide represented by the
following Structural Formula: ##STR00703## comprising the step of
reacting a thioamide represented by the following Structural
Formula: ##STR00704## with hydrazine, wherein ring A is an aryl or
a heteroaryl optionally substituted with one or more substituents
in addition to R.sub.3; R.sub.3 is --OR.sub.26, --SR.sub.26,
--O(CH.sub.2).sub.mOR.sub.A, --O(CH.sub.2).sub.mSR.sub.B,
--O(CH.sub.2).sub.mNR.sub.7R.sub.C, --S(CH.sub.2).sub.mOR.sub.A,
--S(CH.sub.2).sub.mSR.sub.B, --S(CH.sub.2).sub.mNR.sub.7R.sub.C,
--OS(O).sub.pR.sub.7, --SS(O).sub.pR.sub.7, --S(O).sub.pOR.sub.7,
--NR.sub.7S(O).sub.pR.sub.7, --OS(O).sub.pNR.sub.10R.sub.11,
--SS(O).sub.pNR.sub.10R.sub.11,
--NR.sub.7S(O).sub.pNR.sub.10R.sub.11, --SS(O).sub.pOR.sub.7,
--NR.sub.7S(O).sub.pOR.sub.7, --OC(S)OR.sub.7, --SC(S)OR.sub.7,
--NR.sub.7C(S)OR.sub.7, --OC(S)NR.sub.10R.sub.11,
--SC(S)NR.sub.10R.sub.11, --NR.sub.7C(S)NR.sub.10R.sub.11,
--OC(NR.sub.8)R.sub.7, --SC(NR.sub.8)R.sub.7,
--NR.sub.7C(NR.sub.8)R.sub.7, --OC(NR.sub.8)OR.sub.7,
--SC(NR.sub.8)OR.sub.7, --NR.sub.7C(NR.sub.8)OR.sub.7,
--OC(NR.sub.8)NR.sub.10R.sub.11, --SC(NR.sub.8)NR.sub.10R.sub.11,
--NR.sub.7C(NR.sub.8)NR.sub.10R.sub.11, --OP(O)(OR.sub.7).sub.2, or
--SP(O)(OR.sub.7).sub.2, --OR.sub.A, --SR.sub.B, --NR.sub.7R.sub.C,
--NR.sub.26R.sub.C, or --N(R.sub.C).sub.2, wherein R.sub.A is a
hydroxyl protecting group; R.sub.B is a thiol protecting group,
R.sub.C, for each occurrence, is H or an amine protecting group,
provided at least one R.sub.C is an amine protecting group; R.sub.5
is an optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, a substituted alkyl, a substituted phenyl, an
optionally substituted heteroaryl, or an optionally substituted 8
to 14 membered aryl; R.sub.7 and R.sub.8, for each occurrence, are,
independently, --H, an optionally substituted alkyl, an optionally
substituted alkenyl, an optionally substituted alkynyl, an
optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted heterocyclyl, an optionally
substituted aryl, an optionally substituted heteroaryl, an
optionally substituted aralkyl, or an optionally substituted
heteraralkyl; R.sub.10 and R.sub.11, for each occurrence, are
independently --H, an optionally substituted alkyl, an optionally
substituted alkenyl, an optionally substituted alkynyl, an
optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted heterocyclyl, an optionally
substituted aryl, an optionally substituted heteroaryl, an
optionally substituted aralkyl, or an optionally substituted
heteraralkyl; or R.sub.10 and R.sub.11 taken together with the
nitrogen to which they are attached, form an optionally substituted
heterocyclyl or an optionally substituted heteroaryl; R.sub.26 is a
C.sub.1-C.sub.6 alkyl; p, for each occurrence, is, independently,
0, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3,
or 4.
9. A method of preparing a triazole compound represented by the
following Structural Formula: ##STR00705## or a tautomer, a
pharmaceutically acceptable salt, a solvate, a clathrate, or a
prodrug thereof, comprising the step of reacting a hydrazonamide
represented by the following Structural Formula: ##STR00706## with
a carbonylation or a thiocarbonylation reagent, wherein: ring A is
an aryl or a heteroaryl optionally substituted with one or more
substituents in addition to R.sub.3; R.sub.3 is --OR.sub.26,
--SR.sub.26, --O(CH.sub.2).sub.mOR.sub.A,
--O(CH.sub.2).sub.mSR.sub.B, --O(CH.sub.2).sub.mNR.sub.7R.sub.C,
--S(CH.sub.2).sub.mOR.sub.A, --S(CH.sub.2).sub.mSR.sub.B,
--S(CH.sub.2).sub.mNR.sub.7R.sub.C, --OS(O).sub.pR.sub.7,
--SS(O).sub.pR.sub.7, --S(O).sub.pOR.sub.7,
--NR.sub.7S(O).sub.pR.sub.7, --OS(O).sub.pNR.sub.10R.sub.11,
--SS(O).sub.pNR.sub.10R.sub.11,
--NR.sub.7S(O).sub.pNR.sub.10R.sub.11, --SS(O).sub.pOR.sub.7,
--NR.sub.7S(O).sub.pOR.sub.7, --OC(S)OR.sub.7, --SC(S)OR.sub.7,
--NR.sub.7C(S)OR.sub.7, --OC(S)NR.sub.10R.sub.11,
--SC(S)NR.sub.10R.sub.11, --NR.sub.7C(S)NR.sub.10R.sub.11,
--OC(NR.sub.8)R.sub.7, --SC(NR.sub.8)R.sub.7,
--NR.sub.7C(NR.sub.8)R.sub.7, --OC(NR.sub.8)OR.sub.7,
--SC(NR.sub.8)OR.sub.7, --NR.sub.7C(NR.sub.8)OR.sub.7,
--OC(NR.sub.8)NR.sub.10R.sub.11, --SC(NR.sub.8)NR.sub.10R.sub.11,
--NR.sub.7C(NR.sub.8)NR.sub.10R.sub.11, --OP(O)(OR.sub.7).sub.2, or
--SP(O)(OR.sub.7).sub.2, --OR.sub.A, --SR.sub.B, --NR.sub.7R.sub.C,
--NR.sub.26R.sub.C or N(R.sub.C).sub.2, wherein R.sub.A is a
hydroxyl protecting group; R.sub.B is a thiol protecting group,
R.sub.C, for each occurrence, is H or an amine protecting group,
provided at least one R.sub.C is an amine protecting group; R.sub.5
is an optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, a substituted alkyl, a substituted phenyl, an
optionally substituted heteroaryl, or an optionally substituted 8
to 14 membered aryl; R.sub.7 and R.sub.8, for each occurrence, are,
independently, --H, an optionally substituted alkyl, an optionally
substituted alkenyl, an optionally substituted alkynyl, an
optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted heterocyclyl, an optionally
substituted aryl, an optionally substituted heteroaryl, an
optionally substituted aralkyl, or an optionally substituted
heteraralkyl; R.sub.10 and R.sub.11, for each occurrence, are
independently --H, an optionally substituted alkyl, an optionally
substituted alkenyl, an optionally substituted alkynyl, an
optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted heterocyclyl, an optionally
substituted aryl, an optionally substituted heteroaryl, an
optionally substituted aralkyl, or an optionally substituted
heteraralkyl; or R.sub.10 and R.sub.11, taken together with the
nitrogen to which they are attached, form an optionally substituted
heterocyclyl or an optionally substituted heteroaryl; R.sub.26 is a
C1-C6 alkyl; p, for each occurrence, is, independently, 0, 1 or 2;
and m, for each occurrence, is independently, 1, 2, 3, or 4.
10.-12. (canceled)
13. A method of preparing of a triazole compound of Structural
Formula (IA), comprising reacting a compound of Structural Formula
(IIA): ##STR00707## with an oxidizing agent, thereby producing a
compound of Structural Formula (IA): ##STR00708## or a tautomer, a
pharmaceutically acceptable salt, a solvate, a clathrate, or a
prodrug thereof, wherein: ring A is an aryl or a heteroaryl,
wherein the aryl or the heteroaryl are optionally further
substituted with one or more substituents in addition to R.sub.20;
R.sub.5 is an optionally substituted cycloalkyl, an optionally
substituted cycloalkenyl, a substituted alkyl, a substituted
phenyl, an optionally substituted heteroaryl or an optionally
substituted 8 to 14 membered aryl; R.sub.20 is --OR.sub.p1,
--NHR.sub.p3 or --N(R.sub.p3).sub.2, wherein R.sub.p1, for each
occurrence, is independently selected from groups suitable for
protecting hydroxyl, and R.sub.p3, for each occurrence, is
independently selected from groups suitable for protecting an amino
group; R.sub.21 is O, NH, or NR.sub.26, and R.sub.21a is OH,
NH.sub.2 or NHR.sub.26; and R.sub.26 is a C1-C6 alkyl.
14. The method of claim 13, wherein the oxidizing agent is
K.sub.3Fe(CN).sub.6, MnO.sub.2, Br.sub.2, N-bromosuccinimide or
N-chlorosuccinimide.
15. (canceled)
16. The method of claim 13, further comprising the step of
deprotecting the compound of Structural Formula (IA) ##STR00709##
thereby producing a compound of Structural Formula (IA')
##STR00710## wherein R.sub.22 is --OH, or --NH.sub.2.
17. The method of claim 16, wherein R.sub.20 is --OR.sub.p1,
R.sub.p1 is a benzyl group and the step of deprotecting comprises
reacting a compound of formula (IA) with hydrogen in the presence
of hydrogenation catalyst.
18. A method of preparing a compound of Structural Formula (IIA),
##STR00711## comprising: reacting a compound of Structural Formula
(IIIA) ##STR00712## with a compound of Structural Formula (IVA)
##STR00713## in the presence of an acid, thereby producing a
compound of formula (IIA), wherein: ring A is an aryl or a
heteroaryl, wherein the aryl or the heteroaryl are optionally
further substituted with one or more substituents in addition to
R.sub.20; R.sub.5 is an optionally substituted cycloalkyl, an
optionally substituted cycloalkenyl, a substituted alkyl, a
substituted phenyl, an optionally substituted heteroaryl or an
optionally substituted 8 to 14 membered aryl; R.sub.20 is
--OR.sub.p1, --NHR.sub.p3 or --N(R.sub.p3).sub.2, wherein R.sub.p1,
for each occurrence, is independently selected from groups suitable
for protecting hydroxyl, and R.sub.p3, for each occurrence, is
independently selected from groups suitable for protecting an amino
group; R.sub.21 is O, NH, or NR.sub.26, and R.sub.21a is OH,
NH.sub.2 or NHR.sub.26; and R.sub.26 is a C1-C6 alkyl.
19. A method of preparing a triazole compound represented by the
following Structural Formula: ##STR00714## or a tautomer, a
pharmaceutically acceptable salt, a solvate, a clathrate, or a
prodrug thereof, wherein the method comprises the step of reacting
a first starting compound represented by the following Structural
Formula: ##STR00715## in the presence of a mercuric salt, with a
second starting compound represented by the following Structural
Formula: ##STR00716## R.sub.1b is --OH, --SH or --NHR.sub.60,
wherein R.sub.60 is H, an optionally substituted alkyl group, or an
optionally substituted cycloalkyl group; ring A is an aryl or a
heteroaryl, wherein the aryl group and the heteroaryl group
represented by ring A is optionally further substituted with one or
more substituents in addition to R.sub.3; R.sub.3b is --OR.sub.100,
--SR.sub.101, --N(R.sub.102).sub.2, --NR.sub.7R.sub.102,
--OR.sub.26, --SR.sub.26, --NR.sub.26R.sub.102,
--O(CH.sub.2).sub.mOR.sub.100, --O(CH.sub.2).sub.mSR.sub.101,
--O(CH.sub.2).sub.mNR.sub.7R.sub.102,
--S(CH.sub.2).sub.mOR.sub.100, S(CH.sub.2).sub.mSR.sub.101,
S(CH.sub.2).sub.mNR.sub.7R.sub.102, --OC(O)NR.sub.10R.sub.11,
--SC(O)NR.sub.10R.sub.11, --NR.sub.7C(O)NR.sub.10R.sub.11,
--OC(O)R.sub.7, --SC(O)R.sub.7, --NR.sub.7C(O)R.sub.7,
--OC(O)OR.sub.7, --SC(O)OR.sub.7, --NR.sub.7C(O)OR.sub.7,
--OCH.sub.2C(O)R.sub.7, --SCH.sub.2C(O)R.sub.7,
--NR.sub.7CH.sub.2C(O)R.sub.7, --OCH.sub.2C(O)OR.sub.7,
--SCH.sub.2C(O)OR.sub.7, --NR.sub.7CH.sub.2C(O)OR.sub.7,
--OCH.sub.2C(O)NR.sub.10R.sub.11, --SCH.sub.2C(O)NR.sub.10R.sub.11,
--NR.sub.7CH.sub.2C(O)NR.sub.10R.sub.11, --OS(O).sub.pR.sub.7,
--SS(O).sub.pR.sub.7, --S(O).sub.pOR.sub.7,
--NR.sub.7S(O).sub.pR.sub.7, --OS(O).sub.pNR.sub.10R.sub.11,
--SS(O).sub.pNR.sub.10R.sub.11,
--NR.sub.7S(O).sub.pNR.sub.10R.sub.11, --OS(O).sub.pOR.sub.7,
--SS(O).sub.pOR.sub.7, --NR.sub.7S(O).sub.pOR.sub.7,
--OC(S)R.sub.7, --SC(S)R.sub.7, --NR.sub.7C(S)R.sub.7,
--OC(S)OR.sub.7, --SC(S)OR.sub.7, --NR.sub.7C(S)OR.sub.7,
--OC(S)NR.sub.10R.sub.11, --SC(S)NR.sub.10R.sub.11,
--NR.sub.7C(S)NR.sub.10R.sub.11, --OC(NR.sub.8)R.sub.7,
--SC(NR.sub.8)R.sub.7, --NR.sub.7C(NR.sub.8)R.sub.7,
--OC(R.sub.8)OR.sub.7, --SC(NR.sub.8)OR.sub.7,
--NR.sub.7C(NR.sub.8)OR.sub.7, --OC(NR.sub.8)NR.sub.10R.sub.11,
--SC(NR.sub.8)NR.sub.10R.sub.11,
--NR.sub.7C(NR.sub.8)NR.sub.10R.sub.11, --OP(O)(OR.sub.7).sub.2, or
--SP(O)(OR.sub.7).sub.2; each R.sub.100, independently, is a
hydroxyl protecting group; each R.sub.101, independently, is a
thiol protecting group; each R.sub.102, independently, is --H or an
amino protecting group, provided that at least one group
represented by R.sub.102 is a protecting group; R.sub.5 is an
optionally substituted aryl group, an optionally substituted
heteroaryl group, an optionally substituted cycloalkyl group, an
optionally substituted cycloakenyl group, or a substituted alkyl
group, wherein each of the aryl group, heteroaryl group, cycloaryl
group, cycloalkyl group, cycloalkenyl group, and alkyl group is
substituted with one or more substituents independently selected
from the group consisting of an optionally substituted alkyl group,
an optionally substituted alkynyl, an optionally substituted
cycloalkyl group, an optionally substituted cycloalkenyl group, an
optionally substituted heteroaryl group, an optionally substituted
aralyalkyl group, or an optionally substituted heteraralkyl group;
R.sub.7 and R.sub.8, for each occurrence, are, independently, --H,
an optionally substituted alkyl, an optionally substituted alkenyl,
an optionally substituted alkynyl, an optionally substituted
cycloalkyl, an optionally substituted cycloalkenyl, an optionally
substituted heterocyclyl, an optionally substituted aryl, an
optionally substituted heteroaryl, an optionally substituted
aralkyl, an optionally substituted heteraralkyl, or R.sub.7, taken
together with the oxygen atom to which it is bonded, forms an
optionally substituted heterocyclyl or an optionally substituted
heteroaryl; R.sub.10 and R.sub.11, for each occurrence, are,
independently, amine protecting group, an optionally substituted
alkyl, an optionally substituted alkenyl, an optionally substituted
alkynyl, an optionally substituted cycloalkyl, an optionally
substituted cycloalkenyl, an optionally substituted heterocyclyl,
an optionally substituted aryl, an optionally substituted
heteroaryl, an optionally substituted aralkyl, or an optionally
substituted heteraralkyl; or R.sub.10 and R.sub.11, taken together
with the nitrogen to which they are attached, form an optionally
substituted heterocyclyl or an optionally substituted heteroaryl;
R.sub.26 is a C1-C6 alkyl group; R.sub.50 is an optionally
substituted alkyl, an optionally substituted alkenyl, an optionally
substituted alkynyl, an optionally substituted cycloalkyl, an
optionally substituted cycloalkenyl, an optionally substituted
heterocyclyl, an optionally substituted aryl, an optionally
substituted heteroaryl, an optionally substituted aralkyl, or an
optionally substituted heteraralkyl; R.sub.51 is .dbd.O, .dbd.S or
.dbd.NR.sub.60; p, for each occurrence, is, independently, 0, 1 or
2; and m, for each occurrence, is, independently, 1, 2, 3, or
4.
20.-27. (canceled)
28. The method of claim 13, wherein R.sub.5 is represented by the
following Structural Formula: ##STR00717## wherein: R.sub.9, for
each occurrence, is independently a substituent selected from:
--OR.sub.p1, --NHR.sub.p3, --N(R.sub.p3).sub.2,
--O(CH.sub.2).sub.mOR.sub.p1, or --(CH.sub.2).sub.mOR.sub.p1; an
optionally substituted alkyl, an optionally substituted alkenyl, an
optionally substituted alkynyl, an optionally substituted
cycloalkyl, an optionally substituted cycloalkenyl, an optionally
substituted heterocyclyl, an optionally substituted aryl, an
optionally substituted heteroaryl, an optionally substituted
aralkyl, an optionally substituted heteraralkyl, alkoxyalkyl,
haloalkoxyalkyl, a heteroalkyl, or a haloalkyl; halo, cyano, nitro,
--NR.sub.10R.sub.11, --OR.sub.7,
--O(CH.sub.2).sub.mNR.sub.7R.sub.p3, --C(O)R.sub.7, --C(O)OR.sub.7;
--C(O)NR.sub.10R.sub.11; --OC(O)R.sub.7, --OC(O)OR.sub.7,
--OC(O)NR.sub.10R.sub.11; --NR.sub.8C(O)R.sub.7,
--NR.sub.7C(O)NR.sub.10R.sub.11, --NR.sub.7C(O)OR.sub.7;
--S(O).sub.pR.sub.7, --OS(O).sub.pR.sub.7, --OS(O).sub.pOR.sub.7,
--OS(O).sub.pNR.sub.10R.sub.11, --S(O).sub.pOR.sub.7,
--S(O).sub.pNR.sub.10R.sub.11, --NR.sub.8S(O).sub.pR.sub.7,
--NR.sub.7S(O).sub.pNR.sub.10R.sub.11, or
--NR.sub.7S(O).sub.pOR.sub.7; or two R.sub.9 groups taken together
with the carbon atoms to which they are attached form a fused ring;
R.sub.7 and R.sub.9, for each occurrence, are, independently, --H,
an optionally substituted alkyl, an optionally substituted alkenyl,
an optionally substituted alkynyl, an optionally substituted
cycloalkyl, an optionally substituted cycloalkenyl, an optionally
substituted heterocyclyl, an optionally substituted aryl, an
optionally substituted heteroaryl, an optionally substituted
aralkyl, or an optionally substituted heteraralkyl; R.sub.10 and
R.sub.11, for each occurrence, are independently --H, an optionally
substituted alkyl, an optionally substituted alkenyl, an optionally
substituted alkynyl, an optionally substituted cycloalkyl, an
optionally substituted cycloalkenyl, an optionally substituted
heterocyclyl, an optionally substituted aryl, an optionally
substituted heteroaryl, an optionally substituted aralkyl, or an
optionally substituted heteraralkyl; or R.sub.10 and R.sub.11,
taken together with the nitrogen to which they are attached, form
an optionally substituted heterocyclyl or an optionally substituted
heteroaryl; p, for each occurrence, is, independently, 0, 1 or 2;
and m, for each occurrence, is independently, 1, 2, 3, or 4.
29.-35. (canceled)
36. The method of claim 13, wherein R.sub.5 is represented by the
following Structural Formula: ##STR00718## wherein: R.sub.33 is H,
--OR.sub.p1, --NHR.sub.p3, --N(R.sub.p3).sub.2, a halo, a lower
alkyl, a lower alkoxy, a lower haloalkyl, or a lower haloalkoxy;
R.sub.34 is H, --OR.sub.p1, --NHR.sub.p3, --N(R.sub.p3).sub.2, a
C1-C6 alkyl, or a lower alkylcarbonyl; and Ring B and Ring C are
optionally substituted with one or more substituents in addition to
R.sub.33 and R.sub.34.
37.-38. (canceled)
39. The method of claim 13, wherein R.sub.5 is selected from the
group consisting of: ##STR00719## wherein: X.sub.6, for each
occurrence, is independently CH, CR.sub.9, N, N(O),
N.sup.+(R.sub.17), provided that at least three X.sub.6 groups are
independently selected from CH and CR.sub.9; X.sub.7, for each
occurrence, is independently CH, CR.sub.9, N, N(O),
N.sup.+(R.sub.17), provided that at least three X.sub.7 groups are
independently selected from CH and CR.sub.9; X.sub.8, for each
occurrence, is independently CH.sub.2, CHR.sub.9, C(R.sub.9).sub.2,
S(O).sub.p, NR.sub.7, or NR.sub.17; X.sub.9, for each occurrence,
is independently N or CH; X.sub.10, for each occurrence, is
independently CH, CR.sub.9, N, N(O), N.sup.+(R.sub.17), provided
that at least one X.sub.10 is selected from CH and CR.sub.9;
R.sub.9, for each occurrence, is independently a substituent
selected from: --OR.sub.p1, --NHR.sub.p3, --N(R.sub.p3).sub.2,
--O(CH.sub.2).sub.mOR.sub.p1, or --(CH.sub.2).sub.mOR.sub.p1; an
optionally substituted alkyl, an optionally substituted alkenyl, an
optionally substituted alkynyl, an optionally substituted
cycloalkyl, an optionally substituted cycloalkenyl, an optionally
substituted heterocyclyl, an optionally substituted aryl, an
optionally substituted heteroaryl, an optionally substituted
aralkyl, an optionally substituted heteraralkyl, alkoxyalkyl,
haloalkoxyalkyl, a heteroalkyl, or a haloalkyl; halo, cyano, nitro,
--NR.sub.10R.sub.11, --OR.sub.7,
--O(CH.sub.2).sub.mNR.sub.7R.sub.p3, --C(O)R.sub.7, --C(O)OR.sub.7;
--C(O)NR.sub.10R.sub.11; --OC(O)R.sub.7, --OC(O)OR.sub.7,
--OC(O)NR.sub.10R.sub.11; --NR.sub.8C(O)R.sub.7,
--NR.sub.7C(O)NR.sub.10R.sub.11, --NR.sub.7C(O)OR.sub.7;
--S(O).sub.pR.sub.7, --OS(O).sub.pR.sub.7, --OS(O).sub.pOR.sub.7,
--OS(O).sub.pNR.sub.10R.sub.11, --S(O).sub.pOR.sub.7,
--S(O).sub.pNR.sub.10R.sub.11, --NR.sub.8S(O).sub.pR.sub.7,
--NR.sub.7S(O).sub.pNR.sub.10R.sub.11, or
--NR.sub.7S(O).sub.pOR.sub.7; or two R.sub.9 groups taken together
with the carbon atoms to which they are attached form a fused ring;
and R.sub.17, for each occurrence, is independently --H, an alkyl,
an aralkyl, --C(O)R.sub.7, --C(O)OR.sub.7, or
--C(O)NR.sub.10R.sub.11; R.sub.7 and R.sub.8, for each occurrence,
are, independently, --H, an optionally substituted alkyl, an
optionally substituted alkenyl, an optionally substituted alkynyl,
an optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted heterocyclyl, an optionally
substituted aryl, an optionally substituted heteroaryl, an
optionally substituted aralkyl, or an optionally substituted
heteraralkyl; R.sub.10 and R.sub.11, for each occurrence, are
independently --H, an optionally substituted alkyl, an optionally
substituted alkenyl, an optionally substituted alkynyl, an
optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted heterocyclyl, an optionally
substituted aryl, an optionally substituted heteroaryl, an
optionally substituted aralkyl, or an optionally substituted
heteraralkyl; or R.sub.10 and R.sub.11, taken together with the
nitrogen to which they are attached, form an optionally substituted
heterocyclyl or an optionally substituted heteroaryl; p, for each
occurrence, is, independently, 0, 1 or 2; and m, for each
occurrence, is independently, 1, 2, 3, or 4.
40.-42. (canceled)
43. The method of claim 13, wherein R.sub.5 is selected from the
group consisting of: ##STR00720## wherein: X.sub.11, for each
occurrence, is independently CH, CR.sub.9, N, N(O), or
N.sup.+(R.sub.17), provided that at least one X.sub.11 is N, N(O),
or N.sup.+(R.sub.17) and at least two X.sub.11 groups are
independently selected from CH and CR.sub.9; X.sub.12, for each
occurrence, is independently CH, CR.sub.9, N, N(O),
N.sup.+(R.sub.17), provided that at least one X.sub.12 group is
independently selected from CH and CR.sub.9; X.sub.13, for each
occurrence, is independently O, S, S(O).sub.p, NR.sub.7, or
NR.sub.17; R.sub.9, for each occurrence, is independently a
substituent selected from: --OR.sub.p1, --NHR.sub.p3,
--N(R.sub.p3).sub.2, --O(CH.sub.2).sub.mOR.sub.p1, or
--(CH.sub.2).sub.mOR.sub.p1; an optionally substituted alkyl, an
optionally substituted alkenyl, an optionally substituted alkynyl,
an optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted heterocyclyl, an optionally
substituted aryl, an optionally substituted heteroaryl, an
optionally substituted aralkyl, an optionally substituted
heteraralkyl, alkoxyalkyl, haloalkoxyalkyl, a heteroalkyl, or a
haloalkyl; halo, cyano, nitro, --NR.sub.10R.sub.11, --OR.sub.7,
--O(CH.sub.2).sub.mNR.sub.7R.sub.p3, --C(O)R.sub.7, --C(O)OR.sub.7;
--C(O)NR.sub.10R.sub.11; --OC(O)R.sub.7, --OC(O)OR.sub.7,
--OC(O)NR.sub.10R.sub.11; --NR.sub.8C(O)R.sub.7,
--NR.sub.7C(O)NR.sub.10R.sub.11, --NR.sub.7C(O)OR.sub.7;
--S(O).sub.pR.sub.7, --OS(O).sub.pR.sub.7, --OS(O).sub.pOR.sub.7,
--OS(O).sub.pNR.sub.10R.sub.11, --S(O).sub.pOR.sub.7,
--S(O).sub.pNR.sub.10R.sub.11, --NR.sub.8S(O).sub.pR.sub.7,
--NR.sub.7S(O).sub.pNR.sub.10R.sub.11, or
--NR.sub.7S(O).sub.pOR.sub.7; R.sub.7 and R.sub.8, for each
occurrence, are, independently, --H, an optionally substituted
alkyl, an optionally substituted alkenyl, an optionally substituted
alkynyl, an optionally substituted cycloalkyl, an optionally
substituted cycloalkenyl, an optionally substituted heterocyclyl,
an optionally substituted aryl, an optionally substituted
heteroaryl, an optionally substituted aralkyl, or an optionally
substituted heteraralkyl; R.sub.10 and R.sub.11, for each
occurrence, are independently --H, an optionally substituted alkyl,
an optionally substituted alkenyl, an optionally substituted
alkynyl, an optionally substituted cycloalkyl, an optionally
substituted cycloalkenyl, an optionally substituted heterocyclyl,
an optionally substituted aryl, an optionally substituted
heteroaryl, an optionally substituted aralkyl, or an optionally
substituted heteraralkyl; or R.sub.10 and R.sub.11, taken together
with the nitrogen to which they are attached, form an optionally
substituted heterocyclyl or an optionally substituted heteroaryl;
R.sub.17, for each occurrence, is independently --H, an alkyl, an
aralkyl, --C(O)R.sub.7, --C(O)OR.sub.7, or --C(O)NR.sub.10R.sub.11;
and p, for each occurrence, is, independently, 0, 1 or 2; and m,
for each occurrence, is independently, 1, 2, 3, or 4.
44.-45. (canceled)
46. The method of claim 13, wherein R.sub.5 is an optionally
substituted cycloalkyl, optionally substituted cycloalkenyl, or a
substituted alkyl, wherein the alkyl group or the cycloalkyl group
is substituted with one or more substituents independently selected
from the group consisting of: --OR.sub.p1, --NHR.sub.p3,
--N(R.sub.p3).sub.2, --O(CH.sub.2).sub.mOR.sub.p1, or
--(CH.sub.2).sub.mOR.sub.p1; an optionally substituted alkyl, an
optionally substituted alkenyl, an optionally substituted alkynyl,
an optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted heterocyclyl, an optionally
substituted aryl, an optionally substituted heteroaryl, an
optionally substituted aralkyl, an optionally substituted
heteraralkyl, alkoxyalkyl, haloalkoxyalkyl, a heteroalkyl, or a
haloalkyl; halo, cyano, nitro, --NR.sub.10R.sub.11, --OR.sub.7,
--O(CH.sub.2).sub.mNR.sub.7R.sub.p3, --C(O)R.sub.7, --C(O)OR.sub.7;
--C(O)NR.sub.10R.sub.11; --OC(O)R.sub.7, --OC(O)OR.sub.7,
--OC(O)NR.sub.10R.sub.11; --NR.sub.8C(O)R.sub.7, --NR.sub.7C(O)NR
OR.sub.11, --NR.sub.7C(O)OR.sub.7; --S(O).sub.pR.sub.7,
--OS(O).sub.pR.sub.7, --OS(O).sub.pOR.sub.7,
--OS(O).sub.pNR.sub.10R.sub.11, --S(O).sub.pOR.sub.7,
--S(O).sub.pNR.sub.10R.sub.11, --NR.sub.8S(O).sub.pR.sub.7,
--NR.sub.7S(O).sub.pNR.sub.10R.sub.11, or
--NR.sub.7S(O).sub.pOR.sub.7; R.sub.7 and R.sub.8, for each
occurrence, are, independently, --H, an optionally substituted
alkyl, an optionally substituted alkenyl, an optionally substituted
alkynyl, an optionally substituted cycloalkyl, an optionally
substituted cycloalkenyl, an optionally substituted heterocyclyl,
an optionally substituted aryl, an optionally substituted
heteroaryl, an optionally substituted aralkyl, or an optionally
substituted heteraralkyl; R.sub.10 and R.sub.11, for each
occurrence, are independently --H, an optionally substituted alkyl,
an optionally substituted alkenyl, an optionally substituted
alkynyl, an optionally substituted cycloalkyl, an optionally
substituted cycloalkenyl, an optionally substituted heterocyclyl,
an optionally substituted aryl, an optionally substituted
heteroaryl, an optionally substituted aralkyl, or an optionally
substituted heteraralkyl; or R.sub.10 and R.sub.11, taken together
with the nitrogen to which they are attached, form an optionally
substituted heterocyclyl or an optionally substituted heteroaryl;
R.sub.17, for each occurrence, is independently --H, an alkyl, an
aralkyl, --C(O)R.sub.7, --C(O)OR.sub.7, or --C(O)NR.sub.10R.sub.11;
and p, for each occurrence, is, independently, 0, 1 or 2; and m,
for each occurrence, is independently, 1, 2, 3, or 4.
47.-50. (canceled)
51. The method of claim 13, wherein R.sub.5 is a phenyl group
substituted with one to five substituents selected from:
--OR.sub.p1, --NHR.sub.p3, --N(R.sub.p3).sub.2,
--O(CH.sub.2).sub.mOR.sub.p1, or --(CH.sub.2).sub.mOR.sub.p1; an
optionally substituted alkyl, an optionally substituted alkenyl, an
optionally substituted alkynyl, an optionally substituted
cycloalkyl, an optionally substituted cycloalkenyl, an optionally
substituted heterocyclyl, an optionally substituted aryl, an
optionally substituted heteroaryl, an optionally substituted
aralkyl, an optionally substituted heteraralkyl, alkoxyalkyl,
haloalkoxyalkyl, a heteroalkyl, or a haloalkyl; halo, cyano, nitro,
--NR.sub.10R.sub.11, --OR.sub.7,
--O(CH.sub.2).sub.mNR.sub.7R.sub.p3, --C(O)R.sub.7, --C(O)OR.sub.7;
--C(O)NR.sub.10R.sub.11; --OC(O)R.sub.7, --OC(O)OR.sub.7,
--OC(O)NR.sub.10R.sub.11; --NR.sub.8C(O)R.sub.7,
--NR.sub.7C(O)NR.sub.10R.sub.11, --NR.sub.7C(O)OR.sub.7;
--S(O).sub.pR.sub.7, --OS(O).sub.pR.sub.7, --OS(O).sub.pOR.sub.7,
--OS(O).sub.pNR.sub.10R.sub.11, --S(O).sub.pOR.sub.7,
--S(O).sub.pNR.sub.10R.sub.11, --NR.sub.8S(O).sub.pR.sub.7,
--NR.sub.7S(O).sub.pNR.sub.10R.sub.11, or
--NR.sub.7S(O).sub.pOR.sub.7; R.sub.7 and R.sub.8, for each
occurrence, are, independently, --H, an optionally substituted
alkyl, an optionally substituted alkenyl, an optionally substituted
alkynyl, an optionally substituted cycloalkyl, an optionally
substituted cycloalkenyl, an optionally substituted heterocyclyl,
an optionally substituted aryl, an optionally substituted
heteroaryl, an optionally substituted aralkyl, or an optionally
substituted heteraralkyl; R.sub.10 and R.sub.11, for each
occurrence, are independently --H, an optionally substituted alkyl,
an optionally substituted alkenyl, an optionally substituted
alkynyl, an optionally substituted cycloalkyl, an optionally
substituted cycloalkenyl, an optionally substituted heterocyclyl,
an optionally substituted aryl, an optionally substituted
heteroaryl, an optionally substituted aralkyl, or an optionally
substituted heteraralkyl; or R.sub.10 and R.sub.11, taken together
with the nitrogen to which they are attached, form an optionally
substituted heterocyclyl or an optionally substituted heteroaryl;
R.sub.17, for each occurrence, is independently --H, an alkyl, an
aralkyl, --C(O)R.sub.7, --C(O)OR.sub.7, or --C(O)NR.sub.10R.sub.11;
and p, for each occurrence, is, independently, 0, 1 or 2; and m,
for each occurrence, is independently, 1, 2, 3, or 4.
52.-53. (canceled)
54. The method of claim 13, wherein ring A is represented by the
following Structural Formula: ##STR00721## wherein: R.sub.6, for
each occurrence, is independently a substituent selected from:
--OR.sub.p1, --NHR.sub.p3, --N(R.sub.p3).sub.2,
--O(CH.sub.2).sub.mOR.sub.p1, or --(CH.sub.2).sub.mOR.sub.p1; an
optionally substituted alkyl, an optionally substituted alkenyl, an
optionally substituted alkynyl, an optionally substituted
cycloalkyl, an optionally substituted cycloalkenyl, an optionally
substituted heterocyclyl, an optionally substituted aryl, an
optionally substituted heteroaryl, an optionally substituted
aralkyl, an optionally substituted heteraralkyl, alkoxyalkyl,
haloalkoxyalkyl, a heteroalkyl, or a haloalkyl; halo, cyano, nitro,
--NR.sub.10R.sub.11, --OR.sub.7, O(CH.sub.2).sub.mNR.sub.7R.sub.p3,
--C(O)R.sub.7, --C(O)OR.sub.7; --C(O)NR.sub.10R.sub.11;
--OC(O)R.sub.7, --OC(O)OR.sub.7, --OC(O)NR.sub.10R.sub.11;
--NR.sub.8C(O)R.sub.7, --NR.sub.7C(O)NR.sub.10R.sub.11,
--NR.sub.7C(O)OR.sub.7; --S(O).sub.pR.sub.7, --OS(O).sub.pR.sub.7,
--OS(O).sub.pOR.sub.7, --OS(O).sub.pNR.sub.10R.sub.11,
--S(O).sub.pOR.sub.7, --S(O).sub.pNR.sub.10R.sub.11,
--NR.sub.8S(O).sub.pR.sub.7, --NR.sub.7S(O).sub.pNR.sub.10R.sub.11,
or --NR.sub.7S(O).sub.pOR.sub.7; and n is zero of an integer from 1
to 4; R.sub.7 and R.sub.8, for each occurrence, are, independently,
--H, an optionally substituted alkyl, an optionally substituted
alkenyl, an optionally substituted alkynyl, an optionally
substituted cycloalkyl, an optionally substituted cycloalkenyl, an
optionally substituted heterocyclyl, an optionally substituted
aryl, an optionally substituted heteroaryl, an optionally
substituted aralkyl, or an optionally substituted heteraralkyl;
R.sub.10 and R.sub.11, for each occurrence, are independently --H,
an optionally substituted alkyl, an optionally substituted alkenyl,
an optionally substituted alkynyl, an optionally substituted
cycloalkyl, an optionally substituted cycloalkenyl, an optionally
substituted heterocyclyl, an optionally substituted aryl, an
optionally substituted heteroaryl, an optionally substituted
aralkyl, or an optionally substituted heteraralkyl; or R.sub.10 and
R.sub.11, taken together with the nitrogen to which they are
attached, form an optionally substituted heterocyclyl or an
optionally substituted heteroaryl; R.sub.17, for each occurrence,
is independently --H, an alkyl, an aralkyl, --C(O)R.sub.7,
--C(O)OR.sub.7, or --C(O)NR.sub.10R.sub.11; and p, for each
occurrence, is, independently, 0, 1 or 2; and m, for each
occurrence, is independently, 1, 2, 3, or 4.
55.-60. (canceled)
61. The method of claim 54, wherein ring A is represented by the
following Structural Formula: ##STR00722## wherein: R.sub.25 is:
--OR.sub.p1, --NHR.sub.p3, --N(R.sub.p3).sub.2,
--O(CH.sub.2).sub.mOR.sub.p1, or --(CH.sub.2).sub.mOR.sub.p1; an
optionally substituted alkyl, an optionally substituted alkenyl, an
optionally substituted alkynyl, an optionally substituted
cycloalkyl, an optionally substituted cycloalkenyl, an optionally
substituted heterocyclyl, an optionally substituted aryl, an
optionally substituted heteroaryl, an optionally substituted
aralkyl, an optionally substituted heteraralkyl, alkoxyalkyl,
haloalkoxyalkyl, a heteroalkyl, or a haloalkyl; halo, cyano, nitro,
--NR.sub.10R.sub.11, --OR.sub.7,
--O(CH.sub.2).sub.mNR.sub.7R.sub.p3, --C(O)R.sub.7, --C(O)OR.sub.7;
--C(O)NR.sub.10R.sub.11; --OC(O)R.sub.7, --OC(O)OR.sub.7,
--OC(O)NR.sub.10R.sub.11; --NR.sub.8C(O)R.sub.7,
--NR.sub.7C(O)NR.sub.10R.sub.11, --NR.sub.7C(O)OR.sub.7;
--S(O).sub.pR.sub.7, --OS(O).sub.pR.sub.7, --OS(O).sub.pOR.sub.7,
--OS(O).sub.pNR.sub.10R.sub.11, --S(O).sub.pOR.sub.7,
--S(O).sub.pNR.sub.10R.sub.11, --NR.sub.8S(O).sub.pR.sub.7,
--NR.sub.7S(O).sub.pNR.sub.10R.sub.11, or
--NR.sub.7S(O).sub.pOR.sub.7; and r is zero or an integer from 1 to
3,
62.-83. (canceled)
84. The method of claim 13, wherein ring A is represented by the
following Structural Formula: ##STR00723## wherein: X.sub.3 and
X.sub.4 are each, independently, N, N(O), N.sup.+(R.sub.17), CH or
CR.sub.6; X.sub.5 is O, S, NR.sub.17, CH.dbd.CH, CH.dbd.CR.sub.6,
CR.sub.6.dbd.CH, CR.sub.6.dbd.CR.sub.6, CH.dbd.N, CR.sub.6.dbd.N,
CH.dbd.N(O), CR.sub.6.dbd.N(O), N.dbd.CH, N.dbd.CR.sub.6,
N(O).dbd.CH, N(O).dbd.CR.sub.6, N.sup.+(R.sub.17).dbd.CH,
N.sup.+(R.sub.17).dbd.CR.sub.6, CH.dbd.N.sup.+(R.sub.17),
CR.sub.6.dbd.N.sup.+(R.sub.17), or N.dbd.N; R.sub.6, for each
occurrence, is independently: --OR.sub.p1, --NHR.sub.p3,
--N(R.sub.p3).sub.2, --O(CH.sub.2).sub.mOR.sub.p1, or
--(CH.sub.2).sub.mOR.sub.p1; an optionally substituted alkyl, an
optionally substituted alkenyl, an optionally substituted alkynyl,
an optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted heterocyclyl, an optionally
substituted aryl, an optionally substituted heteroaryl, an
optionally substituted aralkyl, an optionally substituted
heteraralkyl, alkoxyalkyl, haloalkoxyalkyl, a heteroalkyl, or a
haloalkyl; halo, cyano, nitro, --NR.sub.10R.sub.11, --OR.sub.7,
--O(CH.sub.2).sub.mNR.sub.7R.sub.p3, --C(O)R.sub.7, --C(O)OR.sub.7;
--C(O)NR.sub.10R.sub.11; --OC(O)R.sub.7, --OC(O)OR.sub.7,
--OC(O)NR.sub.10R.sub.11; --NR.sub.8C(O)R.sub.7,
--NR.sub.7C(O)NR.sub.10R.sub.11, --NR.sub.7C(O)OR.sub.7;
--S(O).sub.pR.sub.7, --OS(O).sub.pR.sub.7, --OS(O).sub.pOR.sub.7,
--OS(O).sub.pNR.sub.10R.sub.11, --S(O).sub.pOR.sub.7,
--S(O).sub.pNR.sub.10R.sub.11, --NR.sub.8(O).sub.pR.sub.7,
--NR.sub.7S(O).sub.pNR.sub.10R.sub.11, or
--NR.sub.7S(O).sub.pOR.sub.7; and n is zero or an integer from 1 to
4; R.sub.7 and R.sub.8, for each occurrence, are, independently,
--H, an optionally substituted alkyl, an optionally substituted
alkenyl, an optionally substituted alkynyl, an optionally
substituted cycloalkyl, an optionally substituted cycloalkenyl, an
optionally substituted heterocyclyl, an optionally substituted
aryl, an optionally substituted heteroaryl, an optionally
substituted aralkyl, or an optionally substituted heteraralkyl;
R.sub.10 and R.sub.11, for each occurrence, are independently --H,
an optionally substituted alkyl, an optionally substituted alkenyl,
an optionally substituted alkynyl, an optionally substituted
cycloalkyl, an optionally substituted cycloalkenyl, an optionally
substituted heterocyclyl, an optionally substituted aryl, an
optionally substituted heteroaryl, an optionally substituted
aralkyl, or an optionally substituted heteraralkyl; or R.sub.10 and
R.sub.11, taken together with the nitrogen to which they are
attached, form an optionally substituted heterocyclyl or an
optionally substituted heteroaryl; R.sub.17, for each occurrence,
is independently --H, an alkyl, an aralkyl, --C(O)R.sub.7,
--C(O)OR.sub.7, or --C(O)NR.sub.10R.sub.11; and p, for each
occurrence, is, independently, 0, 1 or 2; and m, for each
occurrence, is independently, 1, 2, 3, or 4.
85.-101. (canceled)
102. The method of claim 13, wherein ring A is represented by the
following Structural Formula: ##STR00724## R.sub.5 is represented
by the following Structural Formula: ##STR00725## wherein: X.sub.41
is O, S, or NR.sub.42; X.sub.42 is CR.sub.44 or N; Y.sub.40 is N or
CR.sub.43; Y.sub.41 is N or CR.sub.45; Y.sub.42, for each
occurrence, is independently N, C or CR.sub.46; R.sub.41 is --H,
--OR.sub.p1, --NHR.sub.p3, --N(R.sub.p3).sub.2,
--O(CH.sub.2).sub.mOR.sub.p1, or --(CH.sub.2).sub.mOR.sub.p1; an
optionally substituted alkyl, an optionally substituted alkenyl, an
optionally substituted alkynyl, an optionally substituted
cycloalkyl, an optionally substituted cycloalkenyl, an optionally
substituted heterocyclyl, an optionally substituted aryl, an
optionally substituted heteroaryl, an optionally substituted
aralkyl, an optionally substituted heteraralkyl, alkoxyalkyl,
haloalkoxyalkyl, a heteroalkyl, or a haloalkyl; halo, cyano, nitro,
--NR.sub.10R.sub.11, --OR.sub.7,
--O(CH.sub.2).sub.mNR.sub.7R.sub.p3, --C(O)R.sub.7, --C(O)OR.sub.7;
--C(O)NR.sub.10R.sub.11; --OC(O)R.sub.7, --OC(O)OR.sub.7,
--OC(O)NR.sub.10R.sub.11; --NR.sub.8C(O)R.sub.7,
--NR.sub.7C(O)NR.sub.10R.sub.11, --NR.sub.7C(O)OR.sub.7;
--S(O).sub.pR.sub.7, --OS(O).sub.pR.sub.7, --OS(O).sub.pOR.sub.7,
--OS(O).sub.pNR.sub.10R.sub.11, --S(O).sub.pOR.sub.7,
--S(O).sub.pNR.sub.10R.sub.11, --NR.sub.8S(O).sub.pR.sub.7,
--NR.sub.7S(O).sub.pNR.sub.10R.sub.11, or
--NR.sub.7S(O).sub.pOR.sub.7; R.sub.42 is --H, --OR.sub.p1,
--NHR.sub.p3, --N(R.sub.p3).sub.2, --O(CH.sub.2).sub.mOR.sub.p1, or
--(CH.sub.2).sub.mOR.sub.p1; an optionally substituted alkyl, an
optionally substituted alkenyl, an optionally substituted alkynyl,
an optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted heterocyclyl, an optionally
substituted aryl, an optionally substituted heteroaryl, an
optionally substituted aralkyl, an optionally substituted
heteraralkyl, alkoxyalkyl, haloalkoxyalkyl, a heteroalkyl, or a
haloalkyl; halo, cyano, nitro, --NR.sub.10R.sub.11, --OR.sub.7,
--O(CH.sub.2).sub.mNR.sub.7R.sub.p3, --C(O)R.sub.7, --C(O)OR.sub.7;
--C(O)NR.sub.10R.sub.11; --OC(O)R.sub.7, --OC(O)OR.sub.7,
--OC(O)NR.sub.10R.sub.11; --NR.sub.8C(O)R.sub.7,
--NR.sub.7C(O)NR.sub.10R.sub.11, --NR.sub.7C(O)OR.sub.7;
--S(O).sub.pR.sub.7, --OS(O).sub.pR.sub.7, --OS(O).sub.pOR.sub.7,
--OS(O).sub.pNR.sub.10R.sub.11, --S(O).sub.pOR.sub.7,
--S(O).sub.pNR.sub.10R.sub.11, --NR.sub.8S(O).sub.pR.sub.7,
--NR.sub.7S(O).sub.pNR.sub.10R.sub.11, or
--NR.sub.7S(O).sub.pOR.sub.7; R.sub.43 and R.sub.44 are,
independently, --H, --OR.sub.p1, --NHR.sub.p3, --N(R.sub.p3).sub.2,
--O(CH.sub.2).sub.mOR.sub.p1, or --(CH.sub.2).sub.mOR.sub.p1; an
optionally substituted alkyl, an optionally substituted alkenyl, an
optionally substituted alkynyl, an optionally substituted
cycloalkyl, an optionally substituted cycloalkenyl, an optionally
substituted heterocyclyl, an optionally substituted aryl, an
optionally substituted heteroaryl, an optionally substituted
aralkyl, an optionally substituted heteraralkyl, alkoxyalkyl,
haloalkoxyalkyl, a heteroalkyl, or a haloalkyl; halo, cyano, nitro,
--NR.sub.10R.sub.11, --OR.sub.7,
--O(CH.sub.2).sub.mNR.sub.7R.sub.p3, --C(O)R.sub.7, --C(O)OR.sub.7;
--C(O)NR.sub.10R.sub.11; --OC(O)R.sub.7, --OC(O)OR.sub.7,
--OC(O)NR.sub.10R.sub.11; --NR.sub.8C(O)R.sub.7,
--NR.sub.7C(O)NR.sub.10R.sub.11, --NR.sub.7C(O)OR.sub.7;
--S(O).sub.pR.sub.7, --OS(O).sub.pR.sub.7, --OS(O).sub.pOR.sub.7,
--OS(O).sub.pNR.sub.10R.sub.11, --S(O).sub.pOR.sub.7,
--S(O).sub.pNR.sub.10R.sub.11, --NR.sub.8S(O).sub.pR.sub.7,
--NR.sub.7S(O).sub.pNR.sub.10R.sub.11, or
--NR.sub.7S(O).sub.pOR.sub.7; or R.sub.43 and R.sub.44 taken
together with the carbon atoms to which they are attached form an
optionally substituted cycloalkenyl, an optionally substituted
aryl, an optionally substituted heterocyclyl, or an optionally
substituted heteroaryl; R.sub.45 is --H, --OR.sub.p1, --NHR.sub.p3,
--N(R.sub.p3).sub.2, --O(CH.sub.2).sub.mOR.sub.p1, or
--(CH.sub.2).sub.mOR.sub.p1; an optionally substituted alkyl, an
optionally substituted alkenyl, an optionally substituted alkynyl,
an optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted heterocyclyl, an optionally
substituted aryl, an optionally substituted heteroaryl, an
optionally substituted aralkyl, an optionally substituted
heteraralkyl, alkoxyalkyl, haloalkoxyalkyl, a heteroalkyl, or a
haloalkyl; halo, cyano, nitro, --NR.sub.10R.sub.11, --OR.sub.7,
--O(CH.sub.2).sub.mNR.sub.7R.sub.p3, --C(O)R.sub.7, --C(O)OR.sub.7;
--C(O)NR.sub.10R.sub.11; --OC(O)R.sub.7, --OC(O)OR.sub.7,
--OC(O)NR.sub.10R.sub.11; --NR.sub.8C(O)R.sub.7,
--NR.sub.7C(O)NR.sub.10R.sub.11, --NR.sub.7C(O)OR.sub.7;
--S(O).sub.pR.sub.7, --OS(O).sub.pR.sub.7, --OS(O).sub.pOR.sub.7,
--OS(O).sub.pNR.sub.10R.sub.11, --S(O).sub.pOR.sub.7,
--S(O).sub.pNR.sub.10R.sub.11, --NR.sub.8S(O).sub.pR.sub.7,
--NR.sub.7S(O).sub.pNR.sub.10R.sub.11, or
--NR.sub.7S(O).sub.pOR.sub.7; R.sub.7 and R.sub.8, for each
occurrence, are, independently, --H, an optionally substituted
alkyl, an optionally substituted alkenyl, an optionally substituted
alkynyl, an optionally substituted cycloalkyl, an optionally
substituted cycloalkenyl, an optionally substituted heterocyclyl,
an optionally substituted aryl, an optionally substituted
heteroaryl, an optionally substituted aralkyl, or an optionally
substituted heteraralkyl; R.sub.10 and R.sub.11, for each
occurrence, are independently --H, an optionally substituted alkyl,
an optionally substituted alkenyl, an optionally substituted
alkynyl, an optionally substituted cycloalkyl, an optionally
substituted cycloalkenyl, an optionally substituted heterocyclyl,
an optionally substituted aryl, an optionally substituted
heteroaryl, an optionally substituted aralkyl, or an optionally
substituted heteraralkyl; or R.sub.10 and R.sub.11, taken together
with the nitrogen to which they are attached, form an optionally
substituted heterocyclyl or an optionally substituted heteroaryl;
R.sub.17, for each occurrence, is independently --H, an alkyl, an
aralkyl, --C(O)R.sub.7, --C(O)OR.sub.7, or --C(O)NR.sub.10R.sub.11;
and p, for each occurrence, is, independently, 0, 1 or 2; and m,
for each occurrence, is independently, 1, 2, 3, or 4.
103.-126. (canceled)
127. The method of claim 102, wherein R.sub.5 is represented by the
following Structural Formula: ##STR00726##
128. The method of claim 127, wherein X.sub.42 is CR.sub.44, and
R.sub.43 and R.sub.44 are, independently, selected from the group
consisting of --H, methyl, ethyl, propyl, isopropyl, cyclopropyl,
methoxy, ethoxy, propoxy, and cyclopropoxy.
129. The method of claim 128, wherein X.sub.42 is CR.sub.44, and
R.sub.43 and R.sub.44, taken together with the carbon atoms to
which they are attached, form a cycloalkenyl, aryl, heterocyclyl,
or heteroaryl ring.
130.-131. (canceled)
132. The method of claim 127, wherein X.sub.42 is N.
133.-140. (canceled)
141. The method of claim 13, wherein the triazole compound is
represented by Structural Formula (XXA), or a tautomer, a
pharmaceutically acceptable salt, solvate, or clathrate or a
prodrug thereof, and the method comprising reacting a compound of
Structural Formula (XXIA): ##STR00727## with an oxidizing agent,
thereby producing the compound of Structural Formula (XXA):
##STR00728## wherein R.sub.p1, for each occurrence, is
independently selected from groups suitable for protecting
hydroxyl.
142.-150. (canceled)
151. A compound represented by the following Structural Formula:
##STR00729## wherein: Z is S or N--NH.sub.2; ring A is an aryl or a
heteroaryl optionally substituted with one or more substituents in
addition to R.sub.3; R.sub.3 is --OR.sub.26, --SR.sub.26,
--O(CH.sub.2).sub.mOR.sub.A, --O(CH.sub.2).sub.mSR.sub.B,
--O(CH.sub.2).sub.mNR.sub.7R.sub.C, S(CH.sub.2).sub.mOR.sub.A,
--S(CH.sub.2).sub.mSR.sub.B, --S(CH.sub.2).sub.mNR.sub.7R.sub.C,
--OS(O).sub.pR.sub.7, --SS(O).sub.pR.sub.7, --S(O).sub.pOR.sub.7,
--NR.sub.7S(O).sub.pR.sub.7, --OS(O).sub.pNR.sub.10R.sub.11,
--SS(O).sub.pNR.sub.10R.sub.11,
--NR.sub.7S(O).sub.pNR.sub.10R.sub.11, --SS(O).sub.pOR.sub.7,
--NR.sub.7S(O).sub.pOR.sub.7, --OC(S)OR.sub.7, --SC(S)OR.sub.7,
--NR.sub.7C(S)OR.sub.7, --OC(S)NR.sub.10R.sub.11,
--SC(S)NR.sub.10R.sub.11, --NR.sub.7C(S)NR.sub.10R.sub.11,
--OC(NR.sub.8)R.sub.7, --SC(NR.sub.8)R.sub.7,
--NR.sub.7C(NR.sub.8)R.sub.7, --OC(NR.sub.8)OR.sub.7,
--SC(NR.sub.8)OR.sub.7, --NR.sub.7C(NR.sub.8)OR.sub.7,
--OC(NR.sub.8)NR.sub.10R.sub.11, --SC(NR.sub.8)NR.sub.10R.sub.11,
--NR.sub.7C(NR.sub.8)NR.sub.10R.sub.11, --OP(O)(OR.sub.7).sub.2, or
--SP(O)(OR.sub.7).sub.2, --OR.sub.A, --SR.sub.B, NR.sub.7R.sub.C,
NR.sub.26R.sub.C or N(R.sub.C).sub.2, wherein R.sub.A is a hydroxyl
protecting group; R.sub.B is a thiol protecting group, R.sub.C, for
each occurrence, is H or an amine protecting group, provided at
least one R.sub.C is an amine protecting group; R.sub.5 is an
optionally substituted heteroaryl, an optionally substituted aryl,
an optionally substituted cycloaliphatic, or an optionally
substituted alkyl; R.sub.7 and R.sub.8, for each occurrence, are,
independently, --H, an optionally substituted alkyl, an optionally
substituted alkenyl, an optionally substituted alkynyl, an
optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted heterocyclyl, an optionally
substituted aryl, an optionally substituted heteroaryl, an
optionally substituted aralkyl, or an optionally substituted
heteraralkyl; R.sub.10 and R.sub.11, for each occurrence, are
independently --H, an optionally substituted alkyl, an optionally
substituted alkenyl, an optionally substituted alkynyl, an
optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted heterocyclyl, an optionally
substituted aryl, an optionally substituted heteroaryl, an
optionally substituted aralkyl, or an optionally substituted
heteraralkyl; or R.sub.10 and R.sub.11, taken together with the
nitrogen to which they are attached, form an optionally substituted
heterocyclyl or an optionally substituted heteroaryl; R.sub.26 is a
C1-C6 alkyl; p, for each occurrence, is, independently, 0, 1 or 2;
and m, for each occurrence, is independently, 1, 2, 3, or 4.
152. A compound represented by the following Structural Formula
(IIA): ##STR00730## wherein: ring A is an aryl or a heteroaryl,
wherein the aryl or the heteroaryl are optionally further
substituted with one or more substituents in addition to R.sub.20;
R.sub.5 is an optionally substituted cycloalkyl, an optionally
substituted cycloalkenyl, a substituted alkyl, a substituted
phenyl, an optionally substituted heteroaryl or an optionally
substituted 8 to 14 membered aryl; R.sub.20 is --OR.sub.p1,
--NHR.sub.p3 or --N(R.sub.p3).sub.2, wherein R.sub.p1, for each
occurrence, is independently selected from groups suitable for
protecting hydroxyl, and R.sub.p3, for each occurrence, is
independently selected from groups suitable for protecting an amino
group; R.sub.21 is O, NH, or NR.sub.26, and R.sub.21a is OH,
NH.sub.2 or NHR.sub.26; and R.sub.26 is a C1-C6 alkyl.
153.-164. (canceled)
Description
RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Application No. 60/808,342, filed on May 25, 2006, U.S. Provisional
Application No. 60/808,376, filed on May 25, 2006, U.S. Provisional
Application No. 60/808,375, filed on May 25, 2006, and U.S.
Provisional Application No. 60/902,031, filed on Feb. 16, 2007. The
entire teachings of the above applications are incorporated herein
by reference.
BACKGROUND OF THE INVENTION
[0002] Certain triazole-based hsp90 inhibitors, such as the
compounds described in U.S. Publication No. 20060167070,
incorporated herein by reference in its entirety, show promise in
the treatment of proliferative disorders, such as cancer. However,
the molecules described in the referenced patent application
contain a triazolone ring system, the construction of which is
difficult. Synthetic processes currently available for preparing
these compounds are unsuitable for commercial scale synthesis.
Therefore, the need exists for improved synthese of these
compounds.
SUMMARY OF THE INVENTION
[0003] The present invention is directed to novel synthetic methods
for preparing certain [1,2,4]-trizole compounds, which are suitable
for industrial-scale synthesis with minimal purification
required.
[0004] One embodiment of the invention is directed to a method
(method I) of preparing a triazole compound represented by
Structural Formula (I):
##STR00008##
or a tautomer, a pharmaceutically acceptable salt, solvate,
clathrate, or a prodrug thereof.
[0005] The method of preparing a [1,2,4]triazole compound comprises
the steps of: [0006] a) reacting an amide represented by Structural
Formula (II):
[0006] ##STR00009## with a thionation reagent to form a thioamide
represented by Structural Formula (III):
##STR00010## [0007] b) reacting the thioamide of Step a) with
hydrazine to form a hydrazonamide represented by the Structural
Formula (IV):
[0007] ##STR00011## [0008] c) reacting the hydrazonamide of step b)
with a carbonylation, a thiocarbonylation reagent or a compound of
structural formula R.sub.7N.dbd.C(X).sub.2 to form the
[1,2,4]triazole compound. Any protecting groups on the product
formed in step c) are removed.
[0009] In Structural Formulas (I)-(IV), variables are defined as
the following: [0010] ring A is an aryl or a heteroaryl optionally
further substituted with one or more substituents in addition to
R.sub.3; [0011] R.sub.3 is --OR.sub.26, --SR.sub.26,
--O(CH.sub.2).sub.mOR.sub.A, O(CH.sub.2).sub.mSR.sub.B,
--O(CH.sub.2).sub.mNR.sub.7R.sub.C, --S(CH.sub.2).sub.mOR.sub.A,
--S(CH.sub.2).sub.mSR.sub.B, --S(CH.sub.2).sub.mNR.sub.7R.sub.C,
--OS(O).sub.pR.sub.7, --SS(O).sub.pR.sub.7, --S(O).sub.pOR.sub.7,
--NR.sub.7S(O).sub.pR.sub.7, --OS(O).sub.pNR.sub.10R.sub.11,
--SS(O).sub.pNR.sub.10R.sub.11,
--NR.sub.7S(O).sub.pNR.sub.10R.sub.11, --SS(O).sub.pOR.sub.7,
--NR.sub.7S(O).sub.pOR.sub.7, --OC(S)OR.sub.7, --SC(S)OR.sub.7,
--NR.sub.7C(S)OR.sub.7, --OC(S)NR.sub.10R.sub.11,
--SC(S)NR.sub.10R.sub.11, --NR.sub.7C(S)NR.sub.10R.sub.11,
--OC(NR.sub.8)R.sub.7, --SC(NR.sub.8)R.sub.7,
--NR.sub.7C(NR.sub.8)R.sub.7, --OC(NR.sub.8)OR.sub.7,
--SC(NR.sub.8)OR.sub.7, --NR.sub.7C(NR.sub.8)OR.sub.7,
--OC(NR.sub.8)NR.sub.10R.sub.11, --SC(NR.sub.8)NR.sub.10R.sub.11,
--NR.sub.7C(NR.sub.8)NR.sub.10R.sub.11, --OP(O)(OR.sub.7).sub.2, or
--SP(O)(OR.sub.7).sub.2, OR.sub.A, SR.sub.B, NR.sub.7R.sub.C,
NR.sub.26R.sub.C, or N(R.sub.C).sub.2, wherein R.sub.A is a
hydroxyl protecting group; R.sub.B is a thiol protecting group,
R.sub.C, for each occurrence, is H or an amine protecting group,
provided at least one R.sub.C is an amine protecting group; [0012]
R.sub.5 is an optionally substituted heteroaryl, an optionally
substituted aryl, an optionally substituted cycloaliphatic, or an
optionally substituted alkyl; [0013] R.sub.7 and R.sub.8, for each
occurrence, are, independently, --H, an optionally substituted
alkyl, an optionally substituted alkenyl, an optionally substituted
alkynyl, an optionally substituted cycloalkyl, an optionally
substituted cycloalkenyl, an optionally substituted heterocyclyl,
an optionally substituted aryl, an optionally substituted
heteroaryl, an optionally substituted aralkyl, or an optionally
substituted heteraralkyl; [0014] R.sub.10 and R.sub.11, for each
occurrence, are independently --H, an optionally substituted alkyl,
an optionally substituted alkenyl, an optionally substituted
alkynyl, an optionally substituted cycloalkyl, an optionally
substituted cycloalkenyl, an optionally substituted heterocyclyl,
an optionally substituted aryl, an optionally substituted
heteroaryl, an optionally substituted aralkyl, or an optionally
substituted heteraralkyl; or R.sub.10 and R.sub.11, taken together
with the nitrogen to which they are attached, form an optionally
substituted heterocyclyl or an optionally substituted heteroaryl;
[0015] R.sub.26 is a C1-C6 alkyl; [0016] p, for each occurrence,
is, independently, 0, 1 or 2; [0017] m, for each occurrence, is
independently, 1, 2, 3, or 4; [0018] in Structural Formula (I),
R.sub.1 is --OH, --SH or --NHR.sub.7; and X is a leaving group.
[0019] More specifically, the present invention is directed to a
method of preparing a triazole compound represented by the
Structural Formula (V):
##STR00012##
or a tautomer, a pharmaceutically acceptable salt, solvate,
clathrate, or a prodrug thereof. The method of preparing the
[1,2,4]triazole compound comprises the steps of: [0020] a) reacting
an amide represented by Structural Formula (VI):
[0020] ##STR00013## with a thionation reagent to form a thioamide
represented by Structural Formula (VII):
##STR00014## [0021] b) reacting the thioamide of step a) with
hydrazine to form a hydrazonamide represented by Structural Formula
(VIII):
[0021] ##STR00015## [0022] c) reacting the hydrazonamide of step b)
with a carbonylation reagent to form a protected triazole compound;
and [0023] d) deprotecting the protected triazole compound formed
in step c) to form the triazole compound; [0024] wherein R.sub.A is
a hydroxyl protecting group.
[0025] Another embodiment of the invention is directed to a method
of preparing the thioamide represented by Structural Formula (III)
by reacting the amide represented by Structural Formula (II) with
thionation reagent.
[0026] The present invention is also directed to a method of
preparing the hydrazonamide represented by Structural Formula (IV)
by reacting the thioamide of Structural Formula (III) with
hydrazine.
[0027] Another embodiment of the invention is directed to a method
of preparing the [1,2,4]triazole compound by reacting the
hydrazonamide of Structural Formula (IV) with a carbonylation
reagent, a thiocarbonylation reagent or an isocyanide.
[0028] Other embodiments of the present invention are synthetic
intermediates in the preparation of the [1,2,4]triazole compound
represented by Structural Formula (III) and Structural Formula (IV)
by the methods disclosed herein.
[0029] In one embodiment, the present invention is a method (method
II) of synthesis of a compound of Structural Formula (IA)
##STR00016##
a tautomer, a pharmaceutically acceptable salt, solvate, clathrate,
or a prodrug thereof, comprising reacting a compound of Structural
Formula (IIA)
##STR00017##
with an oxidizing agent, thereby producing a compound of Structural
Formula (IA). In Structural Formulas (IA) and (IIA):
[0030] ring A is an aryl or a heteroaryl, wherein the aryl or the
heteroaryl are optionally further substituted with one or more
substituents in addition to R.sub.20;
[0031] R.sub.5 is an optionally substituted cycloalkyl, an
optionally substituted cycloalkenyl, a substituted alkyl, a
substituted phenyl, an optionally substituted heteroaryl or an
optionally substituted 8 to 14 membered aryl;
[0032] R.sub.20 is --OR.sub.p1, --NHR.sub.p3 or
--N(R.sub.p3).sub.2, wherein R.sub.p1, for each occurrence, is
independently selected from groups suitable for protecting
hydroxyl, and R.sub.p3, for each occurrence, is independently
selected from groups suitable for protecting an amino group;
[0033] R.sub.21 is O, NH, or NR.sub.26, and R.sub.21a is OH,
NH.sub.2 or NHR.sub.26; and
[0034] R.sub.26 is a C1-C6 alkyl.
[0035] In another embodiment, the present invention is a method of
synthesis of a compound of Structural Formula (IIA),
##STR00018##
comprising reacting a compound of Structural Formula (IIIA)
##STR00019##
with a compound of Structural Formula (IVA)
##STR00020##
in the presence of an acid, thereby producing a compound of
Structural Formula (IIA). The values of the substituents in
Structural Formulas (IIIA) and (IVA) are as defined with reference
to Structural Formulas (IIA) and (IA).
[0036] In another embodiment, the present invention is a method of
synthesis of a compound of Structural Formula (XXXIA)
##STR00021##
comprising the step of reacting the compound of for Structural
Formula (XXXA)
##STR00022##
with POCl.sub.3 in dimethyl formamide (DMF). Substituents R.sub.301
and R.sub.302 are each independently --H, an alkyl, an aryl, a
heteroaryl, an aralkyl, a heteraralkyl, each optionally substituted
by one or more of an alkyl, alkoxy, haloalkyl, halogen nitro, cyano
or alkyl alkanoate groups.
[0037] In another embodiment, the present invention is a method of
synthesis of the compound of Structural Formula (XXA)
##STR00023##
comprising reacting a compound of Structural Formula (XXIA)
##STR00024##
with an oxidizing agent, thereby producing a compound of formula
(XXA).
[0038] In another embodiment, the present invention is a compound
of Structural Formula (IIA):
##STR00025##
The values and the preferred values of the substituents in
Structural Formula (IIA) are as defined above.
[0039] Another embodiment of the present invention is directed to a
method (method III) of preparing a compound thereof represented by
the following Structural Formula:
##STR00026##
or a tautomer, a pharmaceutically acceptable salt, solvate,
clathrate, or a prodrug thereof. The method comprises the step of
reacting a first starting compound represented by the following
Structural Formula:
##STR00027##
in the presence of a mercuric salt, with a second starting compound
represented by the following Structural Formula:
##STR00028##
[0040] R.sub.1b is --OH, --SH or --NHR.sub.60; preferably, R.sub.1b
is --OH or --SH.
[0041] R.sub.60 is H, an optionally substituted alkyl group, or an
optionally substituted cycloalkyl group.
[0042] Ring A is an aryl or a heteroaryl, wherein the aryl group
and the heteroaryl group represented by ring A is optionally
further substituted with one or more substituents in addition to
R.sub.3b.
[0043] R.sub.3b is --OR.sub.100, --SR.sub.101,
--N(R.sub.102).sub.2, --NR.sub.7R.sub.102, --OR.sub.26,
--SR.sub.26, --NR.sub.26R.sub.102, --O(CH.sub.2).sub.mOR.sub.100,
O(CH.sub.2).sub.mSR.sub.101, --O(CH.sub.2).sub.mNR.sub.7R.sub.102,
--S(CH.sub.2).sub.mOR.sub.100, S(CH.sub.2).sub.mSR.sub.101,
--S(CH.sub.2).sub.mNR.sub.7R.sub.102, --OC(O)NR.sub.10R.sub.11,
--SC(O)NR.sub.10R.sub.11, --NR.sub.7C(O)NR.sub.10R.sub.11,
--OC(O)R.sub.7, --SC(O)R.sub.7, --NR.sub.7C(O)R.sub.7,
--OC(O)OR.sub.7, --SC(O)OR.sub.7, --NR.sub.7C(O)OR.sub.7,
--OCH.sub.2C(O)R.sub.7, --SCH.sub.2C(O)R.sub.7,
--NR.sub.7CH.sub.2C(O)R.sub.7, --OCH.sub.2C(O)OR.sub.7,
--SCH.sub.2C(O)OR.sub.7, --NR.sub.7CH.sub.2C(O)OR.sub.7,
--OCH.sub.2C(O)NR.sub.10R.sub.11, --SCH.sub.2C(O)NR.sub.10R.sub.11,
--NR.sub.7CH.sub.2C(O)NR.sub.10R.sub.11, --OS(O).sub.pR.sub.7,
--SS(O).sub.pR.sub.7, --S(O).sub.pOR.sub.7,
--NR.sub.7S(O).sub.pR.sub.7, --OS(O).sub.pNR.sub.10R.sub.11,
--SS(O).sub.pNR.sub.10R.sub.11,
--NR.sub.7S(O).sub.pNR.sub.10R.sub.11, --OS(O).sub.pOR.sub.7,
--SS(O).sub.pOR.sub.7, --NR.sub.7S(O).sub.pOR.sub.7,
--OC(S)R.sub.7, --SC(S)R.sub.7, --NR.sub.7C(S)R.sub.7,
--OC(S)OR.sub.7, --SC(S)OR.sub.7, --NR.sub.7C(S)OR.sub.7,
--OC(S)NR.sub.10R.sub.11, --SC(S)NR.sub.10R.sub.11,
--NR.sub.7C(S)NR.sub.10R.sub.11, --OC(NR.sub.8)R.sub.7,
--SC(NR.sub.8)R.sub.7, --NR.sub.7C(NR.sub.8)R.sub.7,
--OC(NR.sub.8)OR.sub.7, --SC(NR.sub.8)OR.sub.7,
--NR.sub.7C(NR.sub.8)OR.sub.7, --OC(NR.sub.8)NR.sub.10R.sub.11,
--SC(NR.sub.8)NR.sub.10R.sub.11,
--NR.sub.7C(NR.sub.8)NR.sub.10R.sub.11, --OP(O)(OR.sub.7).sub.2, or
--SP(O)(OR.sub.7).sub.2. Preferably, R.sub.3b is --OR.sub.100,
--SR.sub.101, --N(R.sub.102).sub.2, --NR.sub.7R.sub.102,
--OR.sub.26, --SR.sub.26, --NR.sub.26R.sub.102,
--O(CH.sub.2).sub.mOR.sub.100, --O(CH.sub.2).sub.mSR.sub.101,
--O(CH.sub.2).sub.mNR.sub.7R.sub.102, S(CH.sub.2).sub.mOR.sub.100,
--S(CH.sub.2).sub.mSR.sub.101, and
--S(CH.sub.2).sub.mNR.sub.7R.sub.102.
[0044] Each R.sub.100, independently, is a hydroxyl protecting
group.
[0045] Each R.sub.101, independently, is a thiol protecting
group.
[0046] Each R.sub.102, independently, is --H or an amino protecting
group, provided that at least one group represented by R.sub.102 is
a protecting group.
[0047] R.sub.5 is an optionally substituted aryl group, an
optionally substituted heteroaryl group, an optionally substituted
cycloalkyl group, an optionally substituted cycloakenyl group, or a
substituted alkyl group, wherein each of the aryl group, heteroaryl
group, cycloaryl group, cycloalkyl group, cycloalkenyl group, and
alkyl group is substituted with one or more substituents
independently selected from the group consisting of an optionally
substituted alkyl group, an optionally substituted alkynyl, an
optionally substituted cycloalkyl group, an optionally substituted
cycloalkenyl group, an optionally substituted heteroaryl group, an
optionally substituted aralyalkyl group, or an optionally
substituted heteraralkyl group.
[0048] R.sub.7 and R.sub.8, for each occurrence, are,
independently, --H, an optionally substituted alkyl, an optionally
substituted alkenyl, an optionally substituted alkynyl, an
optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted heterocyclyl, an optionally
substituted aryl, an optionally substituted heteroaryl, an
optionally substituted aralkyl, an optionally substituted
heteraralkyl, or R.sub.7, taken together with the oxygen atom to
which it is bonded, forms an optionally substituted heterocyclyl or
an optionally substituted heteroaryl.
[0049] R.sub.10 and R.sub.11, for each occurrence, are,
independently, amine protecting group, an optionally substituted
alkyl, an optionally substituted alkenyl, an optionally substituted
alkynyl, an optionally substituted cycloalkyl, an optionally
substituted cycloalkenyl, an optionally substituted heterocyclyl,
an optionally substituted aryl, an optionally substituted
heteroaryl, an optionally substituted aralkyl, or an optionally
substituted heteraralkyl; or R.sub.10 and R.sub.11, taken together
with the nitrogen to which they are attached, form an optionally
substituted heterocyclyl or an optionally substituted
heteroaryl.
[0050] R.sub.26 is a lower alkyl group.
[0051] R.sub.50 is an optionally substituted alkyl, an optionally
substituted alkenyl, an optionally substituted alkynyl, an
optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted heterocyclyl, an optionally
substituted aryl, an optionally substituted heteroaryl, an
optionally substituted aralkyl, or an optionally substituted
heteraralkyl.
[0052] R.sub.51 is .dbd.O, .dbd.S or .dbd.NR.sub.60.
[0053] p, for each occurrence, is, independently, 0, 1 or 2.
[0054] m, for each occurrence, is, independently, 1, 2, 3, or
4.
[0055] In another embodiment, the present invention is directed to
a method of preparing a compound thereof represented by the
following Structural Formula:
##STR00029##
[0056] or a tautomer, a pharmaceutically acceptable salt, solvate,
clathrate, or a prodrug thereof. The method comprises the step of
reacting a first starting compound represented by the following
Structural Formula:
##STR00030##
in the presence of a mercuric salt, with a second starting compound
represented by the following structural formula
##STR00031##
[0057] Each R.sub.100, independently, is a hydroxyl protecting
group; and R.sub.50 is an alkyl.
[0058] In alternative embodiment, the present invention is directed
to a method of preparing a compound thereof represented by the
following Structural Formula:
##STR00032##
[0059] or a tautomer, a pharmaceutically acceptable salt, solvate,
clathrate, or a prodrug thereof. The method comprises the steps of:
[0060] 1) reacting a thionation reagent with a compound represented
by the following Structural Formula:
[0060] ##STR00033## thereby forming a first product represented by
the following Structural Formula:
##STR00034## [0061] 2) in the presence of a mercuric salt, reacting
the first product with
[0061] ##STR00035## thereby forming a second product represented by
the following Structural Formula:
##STR00036## [0062] 3) deprotecting the second product, thereby
forming the compound represented by Structural Formula (XIB).
[0063] Values for ring A, R.sub.3b, R.sub.5, R.sub.7, R.sub.8,
R.sub.10, R.sub.11, R.sub.26, R.sub.50, R.sub.51, R.sub.100,
R.sub.101, R.sub.102, p, and m are as described above in Structural
Formulas (IB)-(IIIB).
[0064] Preferably, R.sub.3b is --OR.sub.100, --SR.sub.101,
--N(R.sub.102).sub.2, --NR.sub.7R.sub.102, --OR.sub.26,
--SR.sub.26, --NR.sub.26R.sub.102, --O(CH.sub.2).sub.mOR.sub.100,
--O(CH.sub.2).sub.mSR.sub.101,
--O(CH.sub.2).sub.mNR.sub.7R.sub.102,
--S(CH.sub.2).sub.mOR.sub.100, --S(CH.sub.2).sub.mSR.sub.101, or
--S(CH.sub.2).sub.mNR.sub.7R.sub.102.
[0065] The methods of the present invention described above
overcomes the problem of poor selectivity and eliminates the need
of high temperature heating in the prior methods. Instead, the
methods provides compounds in high yield and with clean
crystallization that is obtained under moderate temperature.
BRIEF DESCRIPTION OF THE DRAWINGS
[0066] FIG. 1 shows a synthetic scheme for preparing
[1,2,4]triazole compound represented by Structural Formula (I).
DETAILED DESCRIPTION OF THE INVENTION
[0067] The present invention is directed to novel synthetic methods
for synthesizing certain [1,2,4]-triazole compounds, which inhibit
the activity of Hsp90 and are useful in the treatment of
proliferative disorders, such as cancer.
[0068] Unless otherwise specified, the terms used herein are
defined as follows:
[0069] As used herein, the term "alkyl" means a saturated straight
chain or branched non-cyclic hydrocarbon having from 1 to 10 carbon
atoms. Representative saturated straight chain alkyls include
methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl,
n-octyl, n-nonyl and n-decyl; while saturated branched alkyls
include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl,
2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl,
4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl,
5-methylhexyl, 2,3-dimethylbutyl, 2,3-dimethylpentyl,
2,4-dimethylpentyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl,
2,5-dimethylhexyl, 2,2-dimethylpentyl, 2,2-dimethylhexyl,
3,3-dimethylpentyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl,
2-ethylpentyl, 3-ethylpentyl, 2-ethylhexyl, 3-ethylhexyl,
4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl,
2-methyl-4-ethylpentyl, 2-methyl-2-ethylhexyl,
2-methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl, 2,2-diethylpentyl,
3,3-diethylhexyl, 2,2-diethylhexyl, 3,3-diethylhexyl and the like.
The term "(C.sub.1-C.sub.6)alkyl" means a saturated straight chain
or branched non-cyclic hydrocarbon having from 1 to 6 carbon atoms.
Representative (C.sub.1-C.sub.6)alkyl groups are those shown above
having from 1 to 6 carbon atoms. Alkyl groups included in compounds
of this invention may be optionally substituted with one or more
substituents.
[0070] As used herein, the term "alkenyl" means a saturated
straight chain or branched non-cyclic hydrocarbon having from 2 to
10 carbon atoms and having at least one carbon-carbon double bond.
Representative straight chain and branched
(C.sub.2-C.sub.10)alkenyls include vinyl, allyl, 1-butenyl,
2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl,
3-methyl-1-butenyl, 2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl,
1-hexenyl, 2-hexenyl, 3-hexenyl, 1-heptenyl, 2-heptenyl,
3-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 1-nonenyl, 2-nonenyl,
3-nonenyl, 1-decenyl, 2-decenyl, 3-decenyl and the like. Alkenyl
groups may be optionally substituted with one or more
substituents.
[0071] As used herein, the term "alkynyl" means a saturated
straight chain or branched non-cyclic hydrocarbon having from 2 to
10 carbon atoms and having at lease one carbon-carbon triple bond.
Representative straight chain and branched alkynyls include
acetylenyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl,
3-methyl-1-butynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 5-hexynyl,
1-heptynyl, 2-heptynyl, 6-heptynyl, 1-octynyl, 2-octynyl,
7-octynyl, 1-nonynyl, 2-nonynyl, 8-nonynyl, 1-decynyl, 2-decynyl,
9-decynyl, and the like. Alkynyl groups may be optionally
substituted with one or more substituents.
[0072] As used herein, the term "cycloalkyl" means a saturated,
mono- or polycyclic alkyl radical having from 3 to 20 carbon atoms.
Representative cycloalkyls include cyclopropyl,
1-methylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, cyclooctyl, cyclononyl, -cyclodecyl,
octahydro-pentalenyl, and the like. Cycloalkyl groups may be
optionally substituted with one or more substituents.
[0073] As used herein, the term "cycloalkenyl" means a mono- or
poly-cyclic non-aromatic alkyl radical having at least one
carbon-carbon double bond in the cyclic system and from 3 to 20
carbon atoms. Representative cycloalkenyls include cyclopentenyl,
cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl,
cycloheptadienyl, cycloheptatrienyl, cyclooctenyl, cyclooctadienyl,
cyclooctatrienyl, cyclooctatetraenyl, cyclononenyl,
cyclononadienyl, cyclodecenyl, cyclodecadienyl,
1,2,3,4,5,8-hexahydronaphthalenyl and the like. Cycloalkenyl groups
may be optionally substituted with one or more substituents.
[0074] As used herein, the term "haloalkyl" means and alkyl group
in which one or more (including all) the hydrogen radicals are
replaced by a halo group, wherein each halo group is independently
selected from --F, --Cl, --Br, and --I. The term "halomethyl" means
a methyl in which one to three hydrogen radical(s) have been
replaced by a halo group. Representative haloalkyl groups include
trifluoromethyl, bromomethyl, 1,2-dichloroethyl, 4-iodobutyl,
2-fluoropentyl, and the like.
[0075] As used herein, an "alkoxy" is an alkyl group which is
attached to another moiety via an oxygen linker.
[0076] As used herein, an "haloalkoxy" is an haloalkyl group which
is attached to another moiety via an oxygen linker.
[0077] As used herein, the term an "aromatic ring" or "aryl" means
a hydrocarbon monocyclic or polycyclic radical in which at least
one ring is aromatic. Examples of suitable aryl groups include, but
are not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl,
azulenyl, and naphthyl, as well as benzo-fused carbocyclic moieties
such as 5,6,7,8-tetrahydronaphthyl. Aryl groups may be optionally
substituted with one or more substituents. In one embodiment, the
aryl group is a monocyclic ring, wherein the ring comprises 6
carbon atoms, referred to herein as "(C.sub.6)aryl."
[0078] As used herein, the term "aralkyl" means an aryl group that
is attached to another group by a (C.sub.1-C.sub.6)alkylene group.
Representative aralkyl groups include benzyl, 2-phenyl-ethyl,
naphth-3-yl-methyl and the like. Aralkyl groups may be optionally
substituted with one or more substituents.
[0079] As used herein, the term "alkylene" refers to an alkyl group
that has two points of attachment. The term
"(C.sub.1-C.sub.6)alkylene" refers to an alkylene group that has
from one to six carbon atoms. Straight chain
(C.sub.1-C.sub.6)alkylene groups are preferred. Non-limiting
examples of alkylene groups include methylene (--CH.sub.2--),
ethylene (--CH.sub.2CH.sub.2--), n-propylene
(--CH.sub.2CH.sub.2CH.sub.2--), isopropylene
(--CH.sub.2CH(CH.sub.3)--), and the like. Alkylene groups may be
optionally substituted with one or more substituents.
[0080] As used herein, the term "heterocyclyl" means a monocyclic
(typically having 3- to 10-members) or a polycyclic (typically
having 7- to 20-members) heterocyclic ring system which is either a
saturated ring or a unsaturated non-aromatic ring. A 3- to
10-membered heterocycle can contain up to 5 heteroatoms; and a 7-
to 20-membered heterocycle can contain up to 7 heteroatoms.
Typically, a heterocycle has at least on carbon atom ring member.
Each heteroatom is independently selected from nitrogen, which can
be oxidized (e.g., N(O)) or quaternized; oxygen; and sulfur,
including sulfoxide and sulfone. The heterocycle may be attached
via any heteroatom or carbon atom. Representative heterocycles
include morpholinyl, thiomorpholinyl, pyrrolidinonyl, pyrrolidinyl,
piperidinyl, piperazinyl, hydantoinyl, valerolactamyl, oxiranyl,
oxetanyl, tetrahydrofuranyl, tetrahydropyranyl,
tetrahydropyrindinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl,
tetrahydrothiopyranyl, and the like. A heteroatom may be
substituted with a protecting group known to those of ordinary
skill in the art, for example, the hydrogen on a nitrogen may be
substituted with a tert-butoxycarbonyl group. Furthermore, the
heterocyclyl may be optionally substituted with one or more
substituents. Only stable isomers of such substituted heterocyclic
groups are contemplated in this definition.
[0081] As used herein, the term "heteroaromatic", "heteroaryl" or
like terms means a monocyclic or polycyclic heteroaromatic ring
comprising carbon atom ring members and one or more heteroatom ring
members. Each heteroatom is independently selected from nitrogen,
which can be oxidized (e.g., N(O)) or quaternized; oxygen; and
sulfur, including sulfoxide and sulfone. Representative heteroaryl
groups include pyridyl, 1-oxo-pyridyl, furanyl, benzo[1,3]dioxolyl,
benzo[1,4]dioxinyl, thienyl, pyrrolyl, oxazolyl, imidazolyl,
thiazolyl, a isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl,
pyridazinyl, pyrimidinyl, pyrazinyl, a triazinyl, triazolyl,
thiadiazolyl, isoquinolinyl, indazolyl, benzoxazolyl, benzofuryl,
indolizinyl, imidazopyridyl, tetrazolyl, benzimidazolyl,
benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, indolyl,
tetrahydroindolyl, azaindolyl, imidazopyridyl, quinazolinyl,
purinyl, pyrrolo[2,3]pyrimidinyl, pyrazolo[3,4]pyrimidinyl,
imidazo[1,2-a]pyridyl, and benzothienyl. In one embodiment, the
heteroaromatic ring is selected from 5-8 membered monocyclic
heteroaryl rings. The point of attachment of a heteroaromatic or
heteroaryl ring to another group may be at either a carbon atom or
a heteroatom of the heteroaromatic or heteroaryl rings. Heteroaryl
groups may be optionally substituted with one or more
substituents.
[0082] As used herein, the term "(C.sub.5)heteroaryl" means an
aromatic heterocyclic ring of 5 members, wherein at least one
carbon atom of the ring is replaced with a heteroatom such as, for
example, oxygen, sulfur or nitrogen. Representative
(C.sub.5)heteroaryls include furanyl, thienyl, pyrrolyl, oxazolyl,
imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl,
pyrazinyl, triazolyl, thiadiazolyl, and the like.
[0083] As used herein, the term "(C.sub.6)heteroaryl" means an
aromatic heterocyclic ring of 6 members, wherein at least one
carbon atom of the ring is replaced with a heteroatom such as, for
example, oxygen, nitrogen or sulfur. Representative
(C.sub.6)heteroaryls include pyridyl, pyridazinyl, pyrazinyl,
triazinyl, tetrazinyl and the like.
[0084] As used herein, the term "heteroaralkyl" means a heteroaryl
group that is attached to another group by a
(C.sub.1-C.sub.6)alkylene. Representative heteroaralkyls include
2-(pyridin-4-yl)-propyl, 2-(thien-3-yl)-ethyl, imidazol-4-yl-methyl
and the like. Heteroaralkyl groups may be optionally substituted
with one or more substituents.
[0085] As used herein, the term "halogen" or "halo" means --F,
--Cl, --Br or --I.
[0086] Suitable substituents for an alkyl, alkylene, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, aralkyl,
heteroaryl, and heteroaralkyl groups include any substituent which
will form a stable compound of the invention. Examples of
substituents for an alkyl, alkylene, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, heterocyclyl, aryl, aralkyl, heteroaryl, and
heteroarylalkyl include R.sup.28 a haloalkyl,
--C(O)NR.sub.28R.sub.29, --C(S)NR.sub.28R.sub.29,
--C(NR.sub.32)NR.sub.28R.sub.29, --NR.sub.30C(O)R.sub.31,
--NR.sub.30C(S)R.sub.31, --NR.sub.30C(NR.sub.32)R.sub.31, halo,
--OR.sub.30, cyano, nitro, haloalkoxy, --C(O)R.sub.30,
--C(S)R.sub.30, --C(NR.sub.32)R.sub.30, --NR.sub.28R.sub.29,
--C(O)OR.sub.30, --C(S)OR.sub.30, --C(NR.sub.32)OR.sub.30,
--OC(O)R.sub.30, --OC(S)R.sub.30, --OC(NR.sub.32)R.sub.30,
--NR.sub.30C(O)NR.sub.28R.sub.29, --NR.sub.30C(S)NR.sub.28R.sub.29,
--NR.sub.30C(NR.sub.32)NR.sub.28R.sub.29, --OC(O)NR.sub.28R.sub.29,
--OC(S)NR.sub.28R.sub.29, --OC(NR.sub.32)NR.sub.28R.sub.29,
--NR.sub.30C(O)OR.sub.31, --NR.sub.30C(S)OR.sub.31,
--NR.sub.30C(NR.sub.32)OR.sub.31, --S(O).sub.hR.sub.30,
--OS(O).sub.pR.sub.30, --NR.sub.3OS(O).sub.pR.sub.30,
--S(O).sub.pNR.sub.28R.sub.29, OS(O).sub.pNR.sub.28R.sub.29, or
--NR.sub.3OS(O).sub.pNR.sub.28R.sub.29, wherein R.sub.28 and
R.sub.29, for each occurrence are, independently, H, an optionally
substituted alkyl, an optionally substituted alkenyl, an optionally
substituted alkynyl, an optionally substituted cycloalkyl, an
optionally substituted cycloalkenyl, an optionally substituted
heterocyclyl, an optionally substituted aryl, an optionally
substituted heteroaryl, an optionally substituted aralkyl, or an
optionally substituted heteraralkyl; or R.sub.28 and R.sub.29 taken
together with the nitrogen to which they are attached is optionally
substituted heterocyclyl or optionally substituted heteroaryl.
Preferably R.sub.28 and R.sub.29, for each occurrence are,
independently, H, alkyl, alkenyl, alkynyl, an cycloalkyl,
cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, or
heteraralkyl; or R.sub.28 and R.sub.29 taken together with the
nitrogen to which they are attached is optionally substituted
heterocyclyl or optionally substituted heteroaryl. In certain
embodiments, the substituents are not --C(O)NR.sub.28R.sub.29,
--NR.sub.30C(O)R.sub.31, --C(O)OR.sub.30,
--NR.sub.30C(O)NR.sub.28R.sub.29, --OC(O)NR.sub.28R.sub.29,
--NR.sub.30C(O)OR.sub.31.
[0087] R.sub.30 and R.sub.31 for each occurrence are,
independently, H, an optionally substituted alkyl, an optionally
substituted alkenyl, an optionally substituted alkynyl, an
optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted heterocyclyl, an optionally
substituted aryl, an optionally substituted heteroaryl, an
optionally substituted aralkyl, or an optionally substituted
heteraralkyl; and
[0088] R.sub.32, for each occurrence is, independently, H, an
optionally substituted alkyl, an optionally substituted alkenyl, an
optionally substituted alkynyl, an optionally substituted
cycloalkyl, an optionally substituted cycloalkenyl, an optionally
substituted heterocyclyl, an optionally substituted aryl, an
optionally substituted heteroaryl, an optionally substituted
aralkyl, an optionally substituted heteraralkyl, --C(O)R.sub.30,
--C(O)NR.sub.28R.sub.29, --S(O).sub.pR.sub.30, or
--S(O).sub.pNR.sub.28R.sub.29;
[0089] p, for each occurrence, is independently, 1 or 2; and
[0090] h is 0, 1 or 2.
[0091] In addition, alkyl, cycloalkyl, alkylene, a heterocyclyl,
and any saturated portion of a alkenyl, cycloalkenyl, alkynyl,
aralkyl, and heteroaralkyl groups, may also be substituted with
.dbd.O, .dbd.S, .dbd.N--R.sub.32.
[0092] When a heterocyclyl, heteroaryl, or heteroaralkyl group
contains a nitrogen atom, it may be substituted or unsubstituted.
When a nitrogen atom in the aromatic ring of a heteroaryl group has
a substituent the nitrogen may be a quaternary nitrogen.
[0093] As used herein, the term "lower" refers to a group having up
to four atoms. For example, a "lower alkyl" refers to an alkyl
radical having from 1 to 4 carbon atoms, "lower alkoxy" refers to
"--O--(C.sub.1-C.sub.4)alkyl and a "lower alkenyl" or "lower
alkynyl" refers to an alkenyl or alkynyl radical having from 2 to 4
carbon atoms, respectively.
[0094] Unless indicated otherwise, the compounds of the invention
containing reactive functional groups (such as (without limitation)
carboxy, hydroxy, thiol, and amino moieties) also include protected
derivatives thereof, such as those found in T. W. Greene,
Protecting Group in Organic Synthesis, Wiley & Sons, Inc. 1999
(hereinafter "Greene"), the entire teachings of which are
incorporated by reference. "Protected derivatives" are those
compounds in which a reactive site or sites are blocked with one or
more protecting groups.
[0095] Examples of suitable protecting groups for hydroxyl groups
include ethers (e.g., methoxymethyl, methylthiomethyl,
(phenyldimethylsilyl)methoxymethyl, benzyloxymethyl,
p-methoxbenzyloxymethyl, p-nitrobenzyloxymethyl,
o-nitrobenzyloxymethyl, (4-methoxyphenoxy)methyl, guaiacolmethyl,
t-butoxymethyl, 4-pentenyloxymethyl, siloxymethyl,
2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl,
bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl,
menthoxymethyl, tetrahydropyranyls, 1-ethoxyethyl,
1-(2-chloroethoxy)ethyl, 1-[2-(trimethylsilyl)ethoxy]ethyl,
1-methyl-1-methoxyethyl, methoxybenzyl, 3,4-dimethoxybenzyl,
o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl,
p-cyanobenzyl, p-phenylbenzyl, 2,6-difluorobenzyl,
p-acylaminobenzyl), silyl ethers (e.g., trimethylsilyl,
triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl,
diethylisopropylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl,
t-butyldiphenylsilyl, tribenzylsilyl, tri-p-xylysilyl,
triphenylsilyl, diphenylmethylsilyl, di-t-butylmethylsilyl,
tris(trimethylsilyl)silyl:sisyl, (2-hydroxystyryl)dimethylsilyl,
and (2-hydroxystyryl)diisopropylsilyl), esters (e.g.,
benzoylformate, acetates, chloroacetate, dichloroacetate,
trichloroacetate, trifluoroacetate, methoxyacetate,
triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate,
phenylacetate, p-P-phenylacetate, and diphenylacetate, nicotinate
and the like), and 3-phenylpropionate), carbonates (e.g.,
methoxylmethyl, 9-fluorenylmethyl, 2,2,2-trichloroethyl,
1,1-dimethyl-2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl,
2-(phenylsulfonyl)ethyl, 2-(triphenylphosphino)ethyl, isobutyl,
vinyl, allyl, p-nitrophenyl, benzyl, p-methoxybenzyl,
3,4-dimethoxybenzyl, o-nitrobenzyl, and p-nitrobenzyl) and other
suitable hydroxyl protecting groups recited in Greene.
[0096] Examples of suitable protecting groups for phenols groups
include ethers (e.g. methyls (e.g. methoxymethyl, benzyloxymethyl,
methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl,
methylthiomethyl, phenylthiomethyl, azidomethyl, cyanomethyl,
2,2-dichloro-1,1-difluoroethyl, 2-chloroethyl, and 2-bromoethyl)
tetrahydropyranyl, and 1-ethoxyethyl), silyl ethers (e.g.
trimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl,
triisopropylsilyl and the like) esters (e.g. formate, acetate,
levulinate, pivaloate, benzoate, 9-fluorenecarboxylate,
xanthenecarboxylate and the like), carbonates (e.g. methyl,
1-adamantyl, t-butyl, 4-methylsulfinylbenzyl,
2,4-dimethylpent-3-yl, 2,2,2-trichloroethyl, vinyl, benzyl, aryl
carbamates and the like).
[0097] Examples of suitable protecting groups for thiol groups
include thioethers (e.g., S-alkyl, S-benzyl, S-p-methoxybenzyl,
S-o- or p-hydroxy- or acetoxybenzyl, S-p-nitrobenzyl,
S-2,4,6-trimethylbenzyl, S-2,4,6-trimethoxybenzyl, S-4-picolyl,
S-2-quinolinylmethyl, S-2-picolyl N-oxido, S-9-anthrylmethyl,
S-phenyl, S-2,4-dinitrophenyl, S-t-butyl, S-methoxymethyl,
S-isobutoxymethyl, and S-benzyloxymethyl), thioesters (e.g.,
S-acetyl, S-benzoyl, S-trifluoroacetyl,
S--N-[[(p-biphenylyl)isopropoxy]carbonyl]-n-methyl-Y-aminothiobutyrate,
S--N-(t-butoxycarbonyl)-n-methyl-.gamma.-aminothiobutyrate, and the
like), thiocarbonated derivatives (e.g.,
S-2,2,2-trichloroethoxycarbonyl, S-t-butoxycarbonyl,
S-benzyloxycarbonyl, S-p-methoxybenzyloxycarbonyl and the like),
thiocarbamate derivatives (e.g., S--(N-ethyl),
S--(N-methoxymethyl)).
[0098] Examples of suitable protecting groups for amino groups
include carbamates (e.g, methyl, ethyl, 9-fluorenylmethyl,
9-(2-sulfo)fluorenylmethyl, 9-(2,7-dibromo)fluorenylmethyl,
17-tetrabenzo[a,c,g,i]fluoemylthmethyl, 2-chloro-3-indenylmethyl,
benz[f]inden-3-ylmethyl-2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrah-
ydrothioxanthyl)]methyl, 1,1-dioxobenzo[b]thiophene-2-ylmethyl,
2,2,2-tricholoroethyl, 2-trimethylsilylethyl, 2-phenylethyl,
1-(1-adamantyl)-1-methylethyl, 2-chloroethyl,
1,1-dimethyl-2-haloethyl, 1,1-dimethyl-2-dibromethyl,
1,1-dimethyl-2,2,2-trichloroethyl, 1-methyl-1-(4-biphenylyl)ethyl,
1-(3,5-di-t-butylphenyl)-1-methylethyl, t-butyl, 1-adamantyl,
2-adamantyl, vinyl, allyl, 1-isopropylallyl, cinnamyl,
4-nitrocinnamyl, benzyl, p-methoxybenzyl, p-nitrobenzyl,
p-bromobenzyl, p-chlorobenzyl, 2,4-dichlorobenzyl, m-nitrophenyl,
3,5-dimethoxybenzyl, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl,
.alpha.-methylnitropiperonyl, o-nitrobenzyl,
3,4-dimethoxy-6-nitrobenzyl, and phenyl(o-nitrophenyl)methyl),
amides (e.g., n-formyl, n-acetyl, n-chloroacetyl,
n-trichloroacetyl, n-trifluoroacetyl, n-phenylacetyl, and
n-3-phenylpropionyl), N-alkyl and N-aryl amines (e.g., n-methyl,
n-t-butyl, n-allyl, n-benzyl, n-4-methoxybenzyl,
n-2,4-dimethoxybenzyl, and n-2-hydroxybenzyl).
[0099] Other suitable protecting groups are well known to those of
ordinary skill in the art and include those found in T. W. Greene,
Protecting Groups in Organic Synthesis, John Wiley & Sons, Inc.
1981, the entire teachings of which are incorporated herein by
reference.
[0100] As used herein, the term "compound(s) of Structural Formulas
(I)-(VIII), (IA), (IA'), (IIA)-(IVA), (XXA), (XXIA), (XXXA),
(XXXIA) or (IB)-(XIB)" and similar terms refers to a compound of
Structural Formulas (I)-(VIII), (IA), (IA'), (IIA)-(IVA), (XXA),
(XXIA), (XXXA), (XXXIA) or (IB)-(XIB), or Tables 1 and 2, or a
tautomer, pharmaceutically acceptable salt, solvate, clathrate,
hydrate, polymorph or prodrug thereof, and also include protected
derivatives thereof.
[0101] The compounds synthesized by the methods of the present
invention may contain one or more chiral centers and/or double
bonds and, therefore, exist as stereoisomers, such as double-bond
isomers (i.e., geometric isomers), enantiomers, or diastereomers.
According to this invention, the chemical structures depicted
herein, including the compounds of this invention, encompass all of
the corresponding compounds' enantiomers, diastereomers and
geometric isomers, that is, both the stereochemically pure form
(e.g., geometrically pure, enantiomerically pure, or
diastereomerically pure) and isomeric mixtures (e.g., enantiomeric,
diastereomeric and geometric isomeric mixtures). In some cases, one
enantiomer, diastereomer or geometric isomer will possess superior
activity or an improved toxicity or kinetic profile compared to
other isomers. In those cases, such enantiomers, diastereomers and
geometric isomers of compounds of this invention are preferred.
[0102] The compounds synthesized by the methods of the present
invention can be obtained in a form of polymorphs, salts, including
a pharmaceutically acceptable salt, solvates or clathrates.
[0103] As used herein, the term "polymorph" means solid crystalline
forms of a compound of the present invention or complex thereof.
Different polymorphs of the same compound can exhibit different
physical, chemical and/or spectroscopic properties. Different
physical properties include, but are not limited to stability
(e.g., to heat or light), compressibility and density (important in
formulation and product manufacturing), and dissolution rates
(which can affect bioavailability). Differences in stability can
result from changes in chemical reactivity (e.g., differential
oxidation, such that a dosage form discolors more rapidly when
comprised of one polymorph than when comprised of another
polymorph) or mechanical characteristics (e.g., tablets crumble on
storage as a kinetically favored polymorph converts to
thermodynamically more stable polymorph) or both (e.g., tablets of
one polymorph are more susceptible to breakdown at high humidity).
Different physical properties of polymorphs can affect their
processing. For example, one polymorph might be more likely to form
solvates or might be more difficult to filter or wash free of
impurities than another due to, for example, the shape or size
distribution of particles of it.
[0104] As used herein, the term "hydrate" means a compound of the
present invention or a salt thereof, that further includes a
stoichiometric or non-stoichiometric amount of water bound by
non-covalent intermolecular forces.
[0105] As used herein, the term "clathrate" means a compound of the
present invention or a salt thereof in the form of a crystal
lattice that contains spaces (e.g., channels) that have a guest
molecule (e.g., a solvent or water) trapped within.
[0106] As used herein and unless otherwise indicated, the term
"prodrug" means a derivative of a compound that can hydrolyze,
oxidize, or otherwise react under biological conditions (in vitro
or in vivo) to provide a compound of this invention. Prodrugs may
become active upon such reaction under biological conditions, or
they may have activity in their unreacted forms. Examples of
prodrugs contemplated in this invention include, but are not
limited to, analogs or derivatives of compounds of Structural
Formulas (I), (V), (IA), (IA'), (XXA), (IB), (IVB), (VIIB), (XIB),
or Tables 1 and 2 that comprise biohydrolyzable moieties such as
biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable
carbamates, biohydrolyzable carbonates, biohydrolyzable ureides,
and biohydrolyzable phosphate analogues. Other examples of prodrugs
include derivatives of compounds of Structural Formulas (I), (V),
(IA), (IA'), (XXA), (IB), (IVB), (VIIB), (XIB) or Tables 1 and 2
that comprise --NO, --NO.sub.2, --ONO, or --ONO.sub.2 moieties.
Prodrugs can typically be prepared using well-known methods, such
as those described by 1 BURGER'S MEDICINAL CHEMISTRY AND DRUG
DISCOVERY (1995) 172-178, 949-982 (Manfred E. Wolff ed., 5.sup.th
ed).
[0107] As used herein and unless otherwise indicated, the terms
"biohydrolyzable amide", "biohydrolyzable ester", "biohydrolyzable
carbamate", "biohydrolyzable carbonate", "biohydrolyzable ureide"
and "biohydrolyzable phosphate analogue" mean an amide, ester,
carbamate, carbonate, ureide, or phosphate analogue, respectively,
that either: 1) does not destroy the biological activity of the
compound and confers upon that compound advantageous properties in
vivo, such as improved water solubility, improved circulating
half-life in the blood (e.g., because of reduced metabolism of the
prodrug), improved uptake, improved duration of action, or improved
onset of action; or 2) is itself biologically inactive but is
converted in vivo to a biologically active compound. Examples of
biohydrolyzable amides include, but are not limited to, lower alkyl
amides, .alpha.-amino acid amides, alkoxyacyl amides, and
alkylaminoalkylcarbonyl amides. Examples of biohydrolyzable esters
include, but are not limited to, lower alkyl esters, alkoxyacyloxy
esters, alkyl acylamino alkyl esters, and choline esters. Examples
of biohydrolyzable carbamates include, but are not limited to,
lower alkylamines, substituted ethylenediamines, aminoacids,
hydroxyalkylamines, heterocyclic and heteroaromatic amines, and
polyether amines.
[0108] As used herein, the term "pharmaceutically acceptable salt,"
is a salt formed from, for example, an acid and a basic group of
one of the compounds of Structural Formulas (I), (V), (IA), (IA'),
(XXA), (IB), (IVB), (VIIB), (XIB), or Tables 1 and 2. Illustrative
salts include, but are not limited, to sulfate, citrate, acetate,
oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate,
acid phosphate, isonicotinate, lactate, salicylate, acid citrate,
tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate,
succinate, maleate, besylate, gentisinate, fumarate, gluconate,
glucaronate, saccharate, formate, benzoate, glutamate,
methanesulfonate, ethanesulfonate, benzenesulfonate,
p-toluenesulfonate, and pamoate (i.e.,
1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. The term
"pharmaceutically acceptable salt" also refers to a salt prepared
from a compound of Structural Formulas (I), (V), (IA), (IA'),
(XXA), (IB), (IVB), (VIIB), (XIB), or Tables 1 and 2 having an
acidic functional group, such as a carboxylic acid functional
group, and a pharmaceutically acceptable inorganic or organic base.
Suitable bases include, but are not limited to, hydroxides of
alkali metals such as sodium, potassium, and lithium; hydroxides of
alkaline earth metal such as calcium and magnesium; hydroxides of
other metals, such as aluminum and zinc; ammonia, and organic
amines, such as unsubstituted or hydroxy-substituted mono-, di-, or
trialkylamines; dicyclohexylamine; tributyl amine; pyridine;
N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis-,
or tris-(2-hydroxy-lower alkyl amines), such as mono-, bis-, or
tris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, or
tris-(hydroxymethyl)methylamine, N,N,-di-lower alkyl-N-(hydroxy
lower alkyl)-amines, such as N,N-dimethyl-N-(2-hydroxyethyl)amine,
or tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids
such as arginine, lysine, and the like. The term "pharmaceutically
acceptable salt" also refers to a salt prepared from a compound of
Structural Formulas (I), (V), (IA), (IA'), (XXA), (IB), (IVB),
(VIIB), (XIB), or Tables 1 and 2 having a basic functional group,
such as an amine functional group, and a pharmaceutically
acceptable inorganic or organic acid. Suitable acids include, but
are not limited to, hydrogen sulfate, citric acid, acetic acid,
oxalic acid, hydrochloric acid (HCl), hydrogen bromide (HBr),
hydrogen iodide (HI), nitric acid, hydrogen bisulfide, phosphoric
acid, lactic acid, salicylic acid, tartaric acid, bitartratic acid,
ascorbic acid, succinic acid, maleic acid, besylic acid, fumaric
acid, gluconic acid, glucaronic acid, formic acid, benzoic acid,
glutamic acid, methanesulfonic acid, ethanesulfonic acid,
benzenesulfonic acid, and p-toluenesulfonic acid.
[0109] As used herein, the term "pharmaceutically acceptable
solvate," is a solvate formed from the association of one or more
pharmaceutically acceptable solvent molecules to one of the
compounds of Structural Formulas (I), (V), (IA), (IA'), (XXA),
(IB), (IVB), (VIIB), (XIB), or Tables 1 and 2. The term solvate
includes hydrates (e.g., hemihydrate, monohydrate, dihydrate,
trihydrate, tetrahydrate, and the like).
[0110] A pharmaceutically acceptable carrier may contain inert
ingredients which do not unduly inhibit the biological activity of
the compounds. The pharmaceutically acceptable carriers should be
biocompatible, i.e., non-toxic, non-inflammatory, non-immunogenic
and devoid of other undesired reactions upon the administration to
a subject. Standard pharmaceutical formulation techniques can be
employed, such as those described in Remington's Pharmaceutical
Sciences, ibid. Suitable pharmaceutical carriers for parenteral
administration include, for example, sterile water, physiological
saline, bacteriostatic saline (saline containing about 0.9% mg/ml
benzyl alcohol), phosphate-buffered saline, Hank's solution,
Ringer's-lactate and the like. Methods for encapsulating
compositions (such as in a coating of hard gelatin or cyclodextran)
are known in the art (Baker, et al., "Controlled Release of
Biological Active Agents", John Wiley and Sons, 1986).
[0111] The compounds synthesized by the methods of the present
invention are defined herein by their chemical structures and/or
chemical names. Where a compound is referred to by both a chemical
structure and a chemical name, and the chemical structure and
chemical name conflict, the chemical structure is determinative of
the compound's identity.
[0112] Only those choices and combinations of substituents that
result in a stable structure are contemplated. Such choices and
combinations will be apparent to those of ordinary skill in the art
and may be determined without undue experimentation.
[0113] As used herein, a composition that "substantially" comprises
a compound means that the composition contains more than about 80%
by weight, more preferably more than about 90% by weight, even more
preferably more than about 95% by weight, and most preferably more
than about 97% by weight of the compound.
[0114] As used herein, a reaction that is "substantially complete"
means that the reaction contains more than about 80% by weight of
the desired product, more preferably more than about 90% by weight
of the desired product, even more preferably more than about 95% by
weight of the desired product, and most preferably more than about
97% by weight of the desired product.
[0115] As used herein, a racemic mixture means about 50% of one
enantiomer and about 50% of is corresponding enantiomer relative to
a chiral center in the molecule. The invention encompasses all
enantiomerically-pure, enantiomerically-enriched,
diastereomerically pure, diastereomerically enriched, and racemic
mixtures of the compounds of the invention.
[0116] Enantiomeric and diastereomeric mixtures can be resolved
into their component enantiomers or diastereomers by well known
methods, such as chiral-phase gas chromatography, chiral-phase high
performance liquid chromatography, crystallizing the compound as a
chiral salt complex, or crystallizing the compound in a chiral
solvent. Enantiomers and diastereomers can also be obtained from
diastereomerically- or enantiomerically-pure intermediates,
reagents, and catalysts by well known asymmetric synthetic
methods.
[0117] In certain instances, tautomeric forms of the compounds
disclosed herein exist, such as the tautomeric structures shown
below:
##STR00037##
[0118] It is to be understood that when a compound is represented
by a structural formula herein, all other tautomeric forms which
may exist for the compound are encompassed by the structural
formula.
[0119] The invention can be understood more fully by reference to
the following detailed description and illustrative examples, which
are intended to exemplify non-limiting embodiments of the
invention.
[0120] The present invention provides novel synthetic methods
(methods I, II and III) suitable for manufacturing [1,2,4]-triazole
compounds on an industrial scale.
[0121] For method I, the synthesis begins with an amidation
reaction of the starting carboxylic acid represented by the
following structural formula:
##STR00038##
with an amine R.sub.5NH.sub.2 to form an amide represented by
Structural Formula (II). The amide is then thionated to form a
thioamide represented by Structural Formula (III). The thioamide is
reacted with hydrazine to form a hydrazonamide compound represented
by Structural Formula (IV), which is cyclized with a carbonylation
reagent, thoicarbonylation reagent or an isocyanide to form the
[1,2,4]trizole compound represented by Structural Formula (I). This
synthesis is shown schematically in FIG. 1. A detailed description
of each reaction in the synthesis is provided below.
[0122] The starting carboxylic acid is first converted to the amide
intermediate represented by Structural Formula (II) by reacting the
starting carboxylic acid of Structural Formula (VI) with the amine
R.sub.5NH.sub.2. Methods for converting a carboxylic acid to an
amide are well known in the art.
[0123] Typically, the carboxylic acid is first converted into a
more reactive derivative with a leaving group that is more readily
displaced by an amine group than --OH. A "leaving group" is a group
which can readily be displaced by a nucleophile. For example, a
carboxylic acid can be converted to a more reactive acyl halide,
typically acyl chloride. Suitable reagents and conditions for
converting a carboxylic acid to an acyl halide are well known in
the art and are described, for example, in March, "Advanced organic
Chemistry--Reactions, Mechanisms and Structure", 5th Edition, John
Wiley & Sons, 2001, pages 523-524, and references cited
therein. Examples of suitable reagents include thionyl chloride,
oxalyl chloride, phosphorus trichloride and phosphorous
pentachloride. Typically, each carboxylic acid group is reacted
with about one equivalent or a slight excess of thionyl chloride,
oxalyl chloride, phosphorus trichloride and phosphorous
pentachloride in an inert solvent such as an ethereal solvent
(e.g., diethyl ether, tetrahydrofuran or 1,4-dioxane), a
halogenated solvent (e.g. methylene chloride or 1,2-dichloroethane)
or aromatic solvent (e.g., benzene or toluene). When the carboxylic
acid is amidated following an initial conversion of carboxylic acid
to acyl halide, stoichiometric amount of the carboxylic acid and
amine can be used. Alternatively, excess of either the carboxylic
acid or amine can be used. When oxalyl chloride is used, a tertiary
amine is often added to accelerate the reaction in quantities
ranging from a catalytic amount to about one equivalent relative to
oxalyl chloride. Typically tertiary amine can be used is
triethylamine. The reaction is generally carried in inert, aprotic
solvents, for example, halogenated solvents such as methylene
chloride, dichloroethane and dimethylformamide. Suitable reaction
temperature generally range from between about 0.degree. C. to
100.degree. C., preferably between about 0.degree. C. to about
ambient temperature.
[0124] Alternatively, the carboxylic acid is first converted into
an "activated ester". An ester --COOR is said to be "activated"
when --OR is readily displaced by an amine or hydrazine. --OR is
more easily displaced as R becomes more electron withdrawing. Some
activated esters are sufficiently stable that they can be isolated,
e.g., esters wherein R is phenyl or substituted phenyl. For
example, diphenylmalonate can be prepared from malonyl chloride and
phenol, both commercially available from Aldrich Chemical Co.,
Milwaukee, Wis., by procedures described above Other activated
esters are more reactive and are generally prepared and used in
situ.
[0125] Formation of an activated ester in situ requires a "coupling
agent", also referred to as a "carboxylic acid activating agent",
which is a reagent that replaces the hydroxyl group of a carboxyl
acid with a group which is susceptible to nucleophilic
displacement. Examples of coupling agents include
1,1'-carbonyldiimidazole (CDI), isobutyl chloroformate,
dimethylaminopropylethyl-carbodiimide (EDC), dicyclohexyl
carbodiimide (DCC). When amidating a carboxylic acid by in situ
activation using a coupling reagent, stoichiometric amount of the
carboxylic acid and amine can be used. Alternatively, excess of
either the carboxylic acid or the amine can be used. The reaction
is generally carried in inert, aprotic solvents, for example,
halogenated solvents such as methylene chloride, dichloroethane and
dimethylformamide.
[0126] The amide of Structural Formula (II) is then reacted with a
thionation reagents to form a thioamide. "Thionation reagent" is a
reagent which, under suitable conditions, can convert a ketone,
ester, or amide into a thioketone, thioester or thioamide,
respectively. There are many thionation reagents known to one of
ordinary skill in the art. Examples include Lawesson's Reagent,
tetraphosphorous pentasulfide, Scheeren's reagent
(P.sub.4S.sub.10--Na.sub.2S), P.sub.4S.sub.10--N(ethyl).sub.3,
Davy's Reagent and Heimgarner's reagent. Also known are conditions
suitable for carrying out these conversions with thionation
reagents. For example, such conditions are disclosed in Fieser and
Fieser, "Reagents for Organic Synthesis", Volume 1, John Wiley
& Sons (1975) page 870-871, Fieser and Fieser, "Reagents for
Organic Synthesis", Volume 5, John Wiley & Sons, (1975) page
653 and publication cited therein. Suitable conditions are also
described in March, "Advanced Organic Chemistry--Reactions,
Mechanisms and Structure", Fifth Edition, John Wiley & Sons,
2001, pages 496, 509, 1184-1185, 1331; Bull. Soc. Chim. Belg.
87:223, 229, 525 (1978), Synthesis 1979: 941 (1979), Tetrahedron
35: 2433 (1979) Tetrahedron 21: 4061 (1980); Tetrahedron, (1985),
41, 2567; Org. Synth. VII, 372; and Tetrahedron Lett., (1986), 27,
3445; and references cited therein. (All of these references are
incorporated herein). There are many thionation reagents known to
one of ordinary skill in the art. Descriptions of these reagents
can also be found in Metzner and Thuillier "Sulfur Reagents in
Organic Synthesis", Academic Press, 1994. The relevant portions of
these publications are incorporated herein by reference.
[0127] To thionate the amide of Structural Formula (II), it may be
desirable to use a slight excess of the amide, for example up to
about 5 equivalents, preferably no more than about 1.5 equivalents.
It may also be desirable to use excess thionation reagent. In some
cases, it may be desirable to use equal equivalents of the amide
and the thionation reagent. Suitable inert solvents include
ethereal solvents (e.g., diethyl ether, tetrahydrofuran, glyme and
1,4-dioxane), aromatic solvents (e.g., benzene and toluene) or
chlorinated solvents (e.g., methylene chloride and
1,2-dichloroethane). The reaction is carried out at temperatures
ranging from about room temperature to about 150.degree. C.,
preferably from about 75.degree. C. to about 125.degree. C. In a
preferred embodiment, the thionation reagent is Lawesson's reagent.
Representative conditions for carrying out thionation reaction are
found in Examples 1 and 2.
[0128] Preferably, the reaction mixture of the amide and thionation
reagent is treated with a water soluble amine after completion of
the reaction. As used herein, a "water soluble amine" may include
any amines (e.g., methylamine), ammonium hydroxide, and hydrazines.
In a more specific embodiment, the water soluble amine is aqueous
ammonium hydroxide. In another more specific embodiment, the water
soluble amine is hydrazine. Typically, excess ammonium hydroxide
solution is used, for example up to 10 equivalents, preferably up
to 5 equivalents, even more preferably up to 2 equivalents.
Detailed description of a representative procedure is found in
Example 1.
[0129] The thioamide of Structural Formula (II) is then converted
to hydrazonamide of Structural Formula (III) by reacting the
thioamide with hydrazine in an inert solvent. Preferably, excess of
hydrazine is used, for example up to 100 equivalents, up to 50
equivalents, up to 10 equivalents. In some cases, it may be
desirable to use excess of thioamide or equal equivalents of
thioamide and hydrazine. Suitable inert solvents include ethereal
solvents (e.g., diethyl ether, tetrahydrofuran, glyme and
1,4-dioxane), aromatic solvents (e.g., benzene and toluene) or
chlorinated solvents (e.g., methylene chloride and
1,2-dichloroethane). The reaction is carried out at temperatures
ranging from about room temperature to about 150.degree. C.,
preferably from about 80.degree. C. to about 100.degree. C.
Representative conditions for carrying out these reactions are
found in Examples 1 and 2.
[0130] The thioamide of Structural Formula (III) is then cyclized
with a carbonylation reagent, a thiocarbonylation reagent or a
compound of structural formula R.sub.7N.dbd.C(X).sub.2, wherein X
is a leaving group, to form the [1,2,4]triazole compound of
Structural Formula (I).
[0131] As used herein, a "carbonylation reagent" is a compound
represented by a structural formula of X--C(.dbd.O)--X, where X a
readily displaced leaving group to facilitate the cyclization
reaction with the hydrazonamide of Structural Formula (IV) to form
the triazole compound of Structural Formula (I), wherein R.sub.1 is
--OH. As used herein, a "leaving group" is a group that can be
displaced by a nucleophile. For example, X can be a imidazoyl
group, a halide, more specifically, a chloride. Examples of
carbonylation reagent may be used include phosgene,
carbonyldiimidazole, diphenyl carbonate,
bis(4-nitrophenyl)carbonate, bis(pentafluorophenyl)carbonate,
bis(trichloromethyl)carbonate, 4-nitrophenyl chloroformate, phenyl
chloroformate, trichloromethyl chloroformate. In a specific
embodiment, the carbonylation reagent is carbonyldiimidazole. The
hydrazonamide of Structural Formula (IV) is converted to the
triazole compound of Structural Formula (I) or a tautomer,
pharmaceutically acceptable salt, solvate, clathrate, or a prodrug
thereof, by reacting the hydrazonamide with a carbonylation reagent
in an inert solvent. Suitable inert solvents include ethereal
solvents (e.g., diethyl ether, tetrahydrofuran, glyme and
1,4-dioxane), aromatic solvents (e.g., benzene and toluene),
chlorinated solvents (e.g., methylene chloride and
1,2-dichloroethane) or ethyl acetate. The reaction is carried out
at temperatures ranging from about room temperature to about
150.degree. C., preferably from about room temperature to about
100.degree. C., more preferably from about room temperature to
about 40.degree. C. Typically, excess of the carbonylation reagent
is used, for example, up to 10 equivalent, more preferably, up to 5
equivalent, even more preferably, up to 1.5 equivalent. In some
case, it may be desirable to use excess of the hydrazonamide, or
equal equivalents of the hydrazonamide and the carbonylation
reagent.
[0132] As used herein, a "thiocarbonylation reagent" is a compound
represented by a structural formula of X--S(.dbd.O)--X, where X a
readily displaced leaving group to facilitate the cyclization
reaction with the hydrazonamide of Structural Formula (IV) to form
the triazole compound of Structural Formula (I), wherein R.sub.1 is
--SH. For example, X can be a imidazoyl group, a halide, more
specifically, a chloride. Examples of thiocarbonylation reagent may
be used include thiocarbonyldiimidazole and thiophosgene. In a
specific embodiment, the thiocarbonylation reagent is
thiocarbonyldiimidazole. The hydrazonamide of Structural Formula
(IV) is converted to the triazole compound of Structural Formula
(I) or a tautomer, pharmaceutically acceptable salt, solvate,
clathrate, or a prodrug thereof, by reacting the hydrazonamide with
a thiocarbonylation reagent in an inert solvent. Suitable inert
solvents include ethereal solvents (e.g., diethyl ether,
tetrahydrofuran, glyme and 1,4-dioxane), aromatic solvents (e.g.,
benzene and toluene), chlorinated solvents (e.g., methylene
chloride and 1,2-dichloroethane) or ethyl acetate. The reaction is
carried out at temperatures ranging from about room temperature to
about 150.degree. C., preferably from about room temperature to
about 100.degree. C., more preferably from about room temperature
to about 40.degree. C. Typically, excess of the carbonylation
reagent is used, for example, up to 10 equivalent, more preferably,
up to 5 equivalent, even more preferably, up to 1.5 equivalent. In
some case, it may be desirable to use excess of the hydrazonamide,
or equal equivalents of the hydrazonamide and the thiocarbonylation
reagent.
[0133] In accordance with the present invention, the hydrazonamide
of Structural Formula (IV) can react with a compound of structural
formula R.sub.7N.dbd.C(X).sub.2 to form the triazole compound of
Structural Formula (I), wherein R.sub.1 is --NHR.sub.7. X is a
readily displaced leaving group that facilitates the cyclization
reaction of R.sub.7N.dbd.C(X).sub.2 with the hydrazonamide of
Structural Formula (IV). For example, X can be a imidazolyl group,
a halide, more specifically a chloride. In a specific embodiment, X
is --Cl. The hydrazomide of Structural Formula (IV) is converted to
the triazole compound of Structural Formula (I) or a tautomer,
pharmaceutically acceptable salt, solvate, clathrate, or a prodrug
thereof, by reacting the hydrazonamide with R.sub.7N.dbd.C(X).sub.2
in an inert solvent. Suitable inert solvents include ethereal
solvents (e.g., diethyl ether, tetrahydrofuran, glyme and
1,4-dioxane), aromatic solvents (e.g., benzene and toluene),
chlorinated solvents (e.g., methylene chloride and
1,2-dichloroethane) or ethyl acetate. The reaction is carried out
at temperatures ranging from about room temperature to about
150.degree. C., preferably from about room temperature to about
100.degree. C., more preferably from about room temperature to
about 40.degree. C., even more preferably, the reaction is carried
out at room temperature. Typically, excess of the carbonylation
reagent is used, for example, up to 5 equivalent, more preferably,
up to 5 equivalent, even more preferably, up to 1.5 equivalent. In
some case, it may be desirable to use excess of the hydrazonamide,
or equal equivalents of the hydrazonamide and the thiocarbonylation
reagent.
[0134] In a specific embodiment, the compound of Structural Formula
(V) is prepared by the disclosed methods. The synthesis of the
compound of Structural Formula (V) comprises an initial step of
thionating the amide of Structural Formula (VI) with a thionation
reagent to form a thioaminde of Structural Formula (VII). The
thioamide is then reacted with hydrazine to form a hydrazonamide of
Structural Formula (VIII). The hydrazonamide is reacted with a
carbonylation reagent to form the compound of Structural Formal
(V). More specifically, the thionation reagent is Lawesson's
reagent and the thionation reagent is carbonyldiimidazole. Any
remaining protecting groups can be removed by standard methods
following formation of the hydrazonamide.
[0135] Method II of the present invention provides a method of
synthesizing a compound of Structural Formula (IA):
##STR00039##
The method comprises reacting a compound of Structural Formula
(IIA)
##STR00040##
with an oxidizing agent, thereby producing a compound of Structural
Formula (IA).
[0136] Specifically, by reacting a compound of Structural Formula
(IIIA)
##STR00041##
[0137] with a compound of Structural Formula (IVA),
##STR00042##
in the presence of an acid, a compound of Structural Formula
(IIA)
##STR00043##
is prepared.
[0138] By reacting a compound of Structural Formula (IIA):
##STR00044##
with an oxidizing agent, a compound of Structural Formula (IA)
##STR00045##
is prepared.
[0139] By removing any protecting groups present in the compound of
Structural Formula (IA) (i.e. "deprotecting the compound"),
##STR00046##
a compound of Structural Formula (IA')
##STR00047##
can be prepared.
[0140] The list of values and preferred values in formulas (IA),
(IA'), (IIA), (IIIA) and (IVA) are defined above. Additionally, in
formula (IA'), R.sub.22 is --OH, or --NH.sub.2. The conditions for
the above reactions will be described below.
[0141] Preferably, the oxidizing agent is K.sub.3Fe(CN).sub.6,
MnO.sub.2, Br.sub.2, N-bromosuccinimide or N-chlorosuccinimide.
More preferably, the oxidizing agent is K.sub.3Fe(CN).sub.6. One
skilled in the art will appreciate that some oxidizing agents
(e.g., K.sub.3Fe(CN).sub.6, MnO.sub.2) are commonly used in
combination with a base. Where a base is used, any organic or
inorganic base can be used, such as a hydroxide base (e.g., NaOH,
KOH, LiOH), amine bases (e.g., ammonia, allylamide, dialkylamine)
or 1,1,1,3,3,3-hexamethyl-disilazane (HMDS). Preferably, the base
is non-nucleophilic. The molar ratio of the base to the oxidizing
agent can be about 5:1, 4:1, 3:1, 2:1; 1:1, 1:2, 1:3, 1:4 or 1:5.
Preferably, equimolar ratio of the oxidizing agent and the base is
used.
[0142] The oxidizing cyclization is generally carried out in polar
solvent. The polar solvent can be a polar protic solvent, such as
water or an alcohol; a polar aprotic aromatic solvent such as
nitrobenzene; or a polar aprotic solvent such as nitromethane,
dimethyl acetamide (DMA), N,N-dimethyl formamide (DMF), dimethyl
sulfoxide (DMSO), hexamethyl phosphoramide (HMPA), or
N-methylpyrrolidone (NMP).
[0143] The molar ratio of the compound of Structural Formula (IIA)
to the oxidizing agent can vary greatly. Although equimolar amount
can be used, the compound of formula (II) is typically used in
excess. Generally, the molar ratio of the compound of formula (II)
to an oxidizing agent can be 1000:1, 900:1, 800:1, 700:1, 600:1,
500:1, 400:1, 300:1, 200:1, 100:1, 50:1, 20:1, 10:1 For example,
when KFe(CN).sub.61NaOH is used, the molar ratio of the compound
(IIA) to KFe(CN).sub.6 is from about 500:1 to about 200:1,
preferably from 350:1 to 300:1; and the molar ration of the
compound (IIA) to NaOH is from about 600:1 to 400:1, preferably
from 550:1 to 450:1.
[0144] Generally, the reaction temperature can be from about
50.degree. C. to about 150.degree. C., preferably, from about
70.degree. C. to about 120.degree. C., more preferably, from about
90.degree. C. to about 110.degree. C.
[0145] Specific examples of a cyclization reaction that converts a
compound of formula (IIA) into a compound of Structural Formula
(IA') are described in the Exemplification section.
[0146] In another embodiment, the compound of Structural Formula
(IIA) is prepared by reacting a compound of Structural Formula
(IIIA)
##STR00048##
with a compound of Structural Formula (IVA),
##STR00049##
in the presence of an acid. Typically, a catalytic amount of acid
is used. "Catalytic amount" typically means a molar ratio from
about 0.1 to about 0.001 of the acid catalyst to the reagents. In
one embodiment, catalytic amount is 0.01 equivalents. Any acid
catalyst can be used, such as organic acids (e.g., formic acid,
acetic acid, trifluoroacetic acid), sulfonic acids (e.g.,
methanesulfonic acid, benzenesulfonic acid and the like), and
mineral acids (sulfuric acid, hydrochloric acid, and the like).
[0147] General conditions for such a reaction are known in the art
and are described, for example, in March, "Advanced Organic
Chemistry--Reactions, Mechanisms and Structure", Third Edition,
John Wiley & Sons, (1985). While excess of one reagent over the
other can be used, typically, equimolar amounts of the compounds of
formulas (IIIA) and (IVA) are employed.
[0148] Any suitable solvent in which reagents are soluble and with
which reagents do not react can be used. The reaction is most
commonly carried out in an alcoholic solvent such as methanol or
ethanol with water as co-solvent (e.g., between 0% and about 50%
volume/volume (v/v), preferably between about 5% and about 15%
v/v).
[0149] The reaction is allowed to proceed at a temperature from
about 30.degree. C. to about 150.degree. C., preferably from about
40.degree. C. to about 130.degree. C., more preferably, from about
50.degree. C. to about 120.degree. C., even more preferably, from
about 60.degree. C. to about 100.degree. C.
[0150] Specific examples of a reaction of a compound of Structural
Formula (IIIA) and a compound of Structural Formula (IVA) are
described in the Exemplification section.
[0151] The compound of Structural Formula (IA) can further be
deprotected, thereby producing a compound of Structural Formula
(IA')
##STR00050##
In Structural Formula (IA'), R.sub.22 is --OH, or --NH.sub.2.
[0152] In another embodiment, the present invention is a method of
synthesis of a compound of Structural Formula (IIA),
##STR00051##
comprising reacting a compound of Structural Formula (IIIA)
##STR00052##
with a compound of Structural Formula (IVA)
##STR00053##
in the presence of acid catalyst. The conditions for this reaction
are described above. Methods of preparing the compound of formula
(IIIA) are illustrated in the Exemplification section and can be
used generally by selecting appropriate starting materials.
[0153] In a specific embodiment, in formulas (IA), (IIA), (IIIA)
and (IVA), R.sub.20 is --OR.sub.p1, R.sub.p1 is a benzyl group and
the step of deprotecting the compound of formula (IA) comprises
reacting a compound of formula (IA) with hydrogen in the presence
of palladium-on-charcoal catalyst.
[0154] In another specific embodiment, formulas (IA), (IIA), (IIIA)
and (IVA), R.sub.20 is --OR.sub.p1, R.sub.p1 is a benzyl group and
the step of deprotecting the compound of formula (IA) comprises
reacting a compound of formula (IA) with ammonium formate in the
presence of a hydrogen catalyst.
[0155] Method III of the present invention begins with an amidation
reaction of the starting carboxylic acid represented by the
following Structural Formula:
##STR00054##
with an amine R.sub.5NH.sub.2 to form an amide represented by
Structural Formula (XIIB). The amide is then thionated to form a
thioamide represented by Structural Formula (IXB).
##STR00055##
Values for R.sub.3b, R.sub.5 and ring A in Structural Formula
(XIIB) are as described in Structural Formulas (IB)-(IIIB).
[0156] The thioamide is reacted with hydrazino carboxylate in the
presence of a mercuric salt to form the [1,2,4]-trizole compound
represented by Structural Formula (IB). This synthesis is shown
schematically in Scheme 1 of Example 5. A detailed description of
each reaction in the synthesis is provided below.
[0157] The starting carboxylic acid is first converted to the amide
intermediate represented by Structural Formula (XIIB) by reacting
the starting carboxylic acid with the amine R.sub.5NH.sub.2.
Methods for converting a carboxylic acid to an amide are well known
in the art and as described above for method I.
[0158] The amide of Structural Formula (XIIB) is then reacted with
a thionation reagents to form a thioamide. "Thionation reagent" is
as described above for method I.
[0159] To thionate the amide of Structural Formula (XIIB), it may
be desirable to use a slight excess of the amide, for example up to
about 5 equivalents, preferably no more than about 1.5 equivalents.
It may also be desirable to use excess thionation reagent. In some
cases, it may be desirable to use equal equivalents of the amide
and the thionation reagent. Suitable inert solvents include
ethereal solvents (e.g., diethyl ether, tetrahydrofuran, glyme and
1,4-dioxane), aromatic solvents (e.g., benzene and toluene) or
chlorinated solvents (e.g., methylene chloride and
1,2-dichloroethane). The reaction is carried out at temperatures
ranging from about room temperature to about 150.degree. C.,
preferably from about 75.degree. C. to about 125.degree. C. In a
preferred embodiment, the thionation reagent is Lawesson's reagent.
Representative conditions for carrying out thionation reaction are
found in Exemplification.
[0160] The thioamide is then reacted with a hydrazino carboxylate
in the presence of a mercuric salt. Although equal molar amounts of
hydrazino carboxylate, thioamide and mercuric salt can be used,
typically, an excess amount of the hydrazino carboxylate and
mercuric salt (e.g., from 1-10 equivalents, 1-5 equivalents or
1-2.5 equivalents) relative to the thioamide is employed for this
synthesis. More typically, at least about two molar equivalents of
the hydrazino carboxylate and mercuric salt relative to the
thioamide, or preferably from 2.0 to about 2.5 equivalents.
Optionally, an excess of the thioamide can be used.
[0161] Suitable solvent can be any inert organic solvent which is
able to dissolve the hydrazino carboxylate, the thioamide and the
mercuric salt when mixed. The organic solvent can generally be
selected from a C1-C4 aliphatic alcohol (e.g., methanol, ethanol,
1-propanol, 2-propanol, or the like), a C1-C4 aliphatic ketone
(e.g., acetone, methyl ethyl ketone, 2-butanone, or the like), a
C2-C8 aliphatic ether (e.g., diethyl ether, THF, dioxane, dipropyl
ether, diisopropyl ether, or the like), a glycol (e.g., ethylene
glycol, propylene glycol, tetramethylene glycol, or the like), an
alkyl glycol ether (e.g., ethylene glycol dimethyl ether, or the
like), an aromatic solvent (e.g., benzene, toluene, or the like)
and acetonitrile. Preferably, the organic solvent can be selected
from tetrahydrofuran or dioxane, and more preferably, dioxane.
[0162] Suitable reaction temperature ranges between about
50.degree. C. and about 150.degree. C., preferably between about
90.degree. C. and about 120.degree. C.
[0163] Suitable mercuric salts include mercuric halides (HgF.sub.2,
HgCl.sub.2 and HgBr.sub.2), mercury acetate and HgO, preferably,
mercuric halides, and more preferably, HgCl.sub.2.
[0164] Optionally, a base such as an amine base (e.g. ammonia,
alkyl amines, dialkyl amines, trialkyl amines, optionally
substituted amines, optionally substituted cycloalkylamines,
N-alkylphthalimide, pyridine, aminopyridines, pyrrolidine,
p-toluidine, aniline, p-nitroaniline, azetidine, morpholine,
piperidine or the like) can be added to the mixture of the
hydrazino carboxylate, thioamide and mercuric salt.
[0165] Typically, concentration of the reagents is between 0.005 M
and 1.0 M, or preferably, between 0.010 M and 0.500 M.
[0166] The synthesis of the triazole compound further includes the
step of deprotecting the compound represented by Structural Formula
(IB). The products of this deprotecting reaction are triazole-based
hsp90 inhibitors.
[0167] Variables in Structural Formulas (I)-(IV), (IA)-(IVA),
(IB)-(IIIB) are as described above.
[0168] In a first specific embodiment, R.sub.5 in Structural
Formulas (I)-(IV), (IA), (IA'), (IIA), (IIIA), (IB), (IIIB),
(VIIB), (VIIIB), (IXB) and (XIB) is optionally substituted
heteroaryl or an optionally substituted 8 to 14 membered aryl. The
remainder of the variables are as described in Structural Formulas
(I)-(IV), (IA), (IA'), (IIA), (IIIA), (IB), (IIIB), (VIIB),
(VIIIB), (IXB) and (XIB).
[0169] In a second specific embodiment, R.sub.5 in Structural
Formulas (I)-(IV), (IA), (IA'), (IIA), (IIIA), (IB), (IIIB),
(VIIB), (VIIIB), (IXB) and (XIB) is a substituted phenyl. The
remainder of the variables are as described in Structural Formulas
(I)-(IV), (IA), (IA'), (IIA), (IIIA), (IB), (IIIB), (VIIB),
(VIIIB), (IXB) and (XIB).
[0170] In a third specific embodiment, R.sub.5 in Structural
Formulas (I)-(IV), (IA), (IA'), (IIA), (IIIA), (IB), (IIIB),
(VIIB), (VIIIB), (IXB) and (XIB) is an optionally substituted
cycloalkyl, an optionally substituted cycloalkenyl, or a
substituted alkyl.
[0171] In a fourth specific embodiment, R.sub.5 in Structural
Formulas (I)-(IV), (IA), (IA'), (IIA), (IIIA), (IB), (IIIB),
(VIIB), (VIIIB), (IXB) and (XIB) is an optionally substituted
naphthyl. The remainder of the variables are as described in
Structural Formulas (I)-(IV), (IA), (IA'), (IIA), (IIIA), (IB),
(IIIB), (VIIB), (VIIIB), (IXB) and (XIB).
[0172] In a fifth specific embodiment, R.sub.5 in Structural
Formulas (I)-(IV), (IA), (IA'), (IIA), (IIIA), (IB), (IIIB),
(VIIB), (VIIB), (IXB) and (XIB) is represented by the following
Structural Formula:
##STR00056##
[0173] wherein:
[0174] for Structural Formulas (I)-(IV), R.sub.9, for each
occurrence, is independently a substituent selected from the group
consisting of an optionally substituted alkyl, an optionally
substituted alkenyl, an optionally substituted alkynyl, an
optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted heterocyclyl, an optionally
substituted aryl, an optionally substituted heteroaryl, an
optionally substituted aralkyl, an optionally substituted
heteraralkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a
haloalkyl, a heteroalkyl, --NR.sub.10R.sub.11 (provided R.sub.10
and R.sub.11 are not --H), --OR.sub.7 (provided R.sub.7 is not
--H), --SR.sub.7 (provided R.sub.7 is not H), --S(O).sub.pR.sub.7,
--OS(O).sub.pR.sub.7, --NR.sub.8S(O).sub.pR.sub.7,
--S(O).sub.pNR.sub.10R.sub.11, --OP(O)(OR.sub.7).sub.2, or
--SP(O)(OR.sub.7).sub.2, --OR.sub.A, --SR.sub.B, --N(R.sub.c).sub.2
or two R.sub.9 groups taken together with the carbon atoms to which
they are attached form a fused ring;
[0175] for Structural Formulas (IA), (IA'), (IIA), and (IIIA),
R.sub.9, for each occurrence, is independently a substituent
selected from: --OR.sub.p1, --NHR.sub.p3, --N(R.sub.p3).sub.2,
--O(CH.sub.2).sub.mOR.sub.p1, or --(CH.sub.2).sub.mOR.sub.p1; an
optionally substituted alkyl, an optionally substituted alkenyl, an
optionally substituted alkynyl, an optionally substituted
cycloalkyl, an optionally substituted cycloalkenyl, an optionally
substituted heterocyclyl, an optionally substituted aryl, an
optionally substituted heteroaryl, an optionally substituted
aralkyl, an optionally substituted heteraralkyl, alkoxyalkyl,
haloalkoxyalkyl, a heteroalkyl, or a haloalkyl; halo, cyano, or
nitro; --NR.sub.10R.sub.11, or --OR.sub.7;
--O(CH.sub.2).sub.mNR.sub.7R.sub.p3; --C(O)R.sub.7, --C(O)OR.sub.7;
--C(O)NR.sub.10R.sub.11; --OC(O)R.sub.7, --OC(O)OR.sub.7,
--OC(O)NR.sub.10R.sub.11; --NR.sub.8C(O)R.sub.7, or
--NR.sub.7C(O)NR.sub.10R.sub.11; --NR.sub.7C(O)OR.sub.7;
--S(O).sub.pR.sub.7, --OS(O).sub.pR.sub.7, --OS(O).sub.pOR.sub.7,
--OS(O).sub.pNR.sub.10R.sub.11, --S(O).sub.pOR.sub.7,
--S(O).sub.pNR.sub.10R.sub.11; --NR.sub.8S(O).sub.pR.sub.7,
--NR.sub.7S(O).sub.pNR.sub.10R.sub.11,
--NR.sub.7S(O).sub.pOR.sub.7. Alternatively, two R.sub.9 groups
taken together with the carbon atoms to which they are attached
form a fused ring;
[0176] R.sub.7 and R.sub.9, for each occurrence, are,
independently, --H, an optionally substituted alkyl, an optionally
substituted alkenyl, an optionally substituted alkynyl, an
optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted heterocyclyl, an optionally
substituted aryl, an optionally substituted heteroaryl, an
optionally substituted aralkyl, or an optionally substituted
heteraralkyl;
[0177] R.sub.10 and R.sub.11, for each occurrence, are
independently --H, an optionally substituted alkyl, an optionally
substituted alkenyl, an optionally substituted alkynyl, an
optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted heterocyclyl, an optionally
substituted aryl, an optionally substituted heteroaryl, an
optionally substituted aralkyl, or an optionally substituted
heteraralkyl;
[0178] or R.sub.10 and R.sub.11, taken together with the nitrogen
to which they are attached, form an optionally substituted
heterocyclyl or an optionally substituted heteroaryl; and
[0179] p, for each occurrence, is, independently, 0, 1 or 2;
and
[0180] m, for each occurrence, is independently, 1, 2, 3, or 4;
[0181] for Structural Formulas (IB), (IIIB), (VIIB), (VIIIB), (IXB)
and (XIB), R.sub.9, for each occurrence, is independently a
substituent selected from the group consisting of an optionally
substituted alkyl, an optionally substituted alkenyl, an optionally
substituted alkynyl, an optionally substituted cycloalkyl, an
optionally substituted cycloalkenyl, an optionally substituted
heterocyclyl, an optionally substituted aryl, an optionally
substituted heteroaryl, an optionally substituted aralkyl, an
optionally substituted heteraralkyl, protected hydroxyalkyl,
alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, a
heteroalkyl, --NR.sub.10R.sub.11, --OR.sub.100 and --C(O)R.sub.7;
or two R.sub.9 groups taken together with the carbon atoms to which
they are attached form a fused ring; and
[0182] m for Structural Formulas (I)-(IV), (IA), (IA'), (IIA),
(IIIA), (IB), (IIIB), (VIIB), (VIIB), (IXB) and (XIB) is zero or an
integer from 1 to 7.
[0183] The remainder of the variables are as described in
Structural Formulas (I)-(IV), (IA), (IA'), (IIA), (IIIA), (IB),
(IIIB), (VIIB), (VIIB), (IXB) and (XIB).
[0184] In a sixth specific embodiment, R.sub.5 in Structural
Formulas (I)-(IV), (IA), (IA'), (IIA), (IIIA), (IB), (IIIB),
(VIIB), (VIIB), (IXB) and (XIB) is represented by the following
Structural Formula:
##STR00057##
[0185] wherein q is zero or an integer from 1 to 7; and
[0186] u is zero or an integer from 1 to 8. The remainder of the
variables are as described in the fifth specific embodiment.
[0187] In a seventh specific embodiment, R.sub.5 in Structural
Formulas (I)-(IV), (IA), (IA'), (IIA), (IIIA), (IB), (IIIB),
(VIIB), (VIIB), (IXB) and (XIB) is an optionally substituted
indolyl. Preferably, R.sub.5 is an indolyl represented by the
following Structural Formula:
##STR00058##
[0188] wherein:
[0189] for Structural Formulas (I)-(IV), R.sub.33 is a halo, a
lower alkyl, a lower alkoxy, a lower haloalkyl, a lower haloalkoxy,
or a lower alkyl sulfanyl;
[0190] R.sub.34 is H, or a lower alkyl;
[0191] Ring B and Ring C are optionally substituted with one or
more substituents in addition to R.sub.33 and R.sub.34. The
remainder of the variables are as described in Structural Formulas
(I)-(IV);
[0192] for Structural Formulas (IA), (IA'), (IIA), and (IIIA),
R.sub.33 is H; --OR.sub.p1, --NHR.sub.p3 or --N(R.sub.p3).sub.2, a
halo, a lower alkyl, a lower alkoxy, a lower haloalkyl, or a lower
haloalkoxy; R.sub.34 is H, --OR.sub.p1, --NHR.sub.p3 or
--N(R.sub.p3).sub.2, a C1-C6 alkyl, or a lower alkylcarbonyl; and
ring B and ring C are optionally substituted with one or more
substituents in addition to R.sub.33 and R.sub.34. The remainder of
the variables are as described in Structural Formulas (IA), (IA'),
(IIA), and (IIIA);
[0193] for Structural Formulas (IB), (IIIB), (VIIB), (VIIIB), (IXB)
and (XIB), R.sub.33 is a halo, a lower alkyl, a lower alkoxy, a
lower haloalkyl, and a lower haloalkoxy, and a lower alkyl
sulfanyl; R.sub.34 is --H, a lower alkyl, or a lower acyl; Rings B
and Ring C are optionally substituted with one or more substituents
in addition to R.sub.33 and R.sub.34; and the remainder of the
variables are as described in Structural Formulas (IB), (IIIB),
(VIIB), (VIIIB), (IXB) and (XIB).
[0194] In a eighth specific embodiment, R.sub.5 in Structural
Formulas (I)-(IV), (IA), (IA'), (IIA), (IIIA), (IB), (IIIB),
(VIIB), (VIIB), (IXB) and (XIB) is a substituted phenyl.
[0195] For Structural Formulas (I)-(IV), the phenyl group is
optionally substituted with:
[0196] i) one substituent selected from nitro, cyano, a haloalkoxy,
an optionally substituted alkenyl, an optionally substituted
alkynyl, an optionally substituted cycloalkyl, an optionally
substituted cycloalkenyl, an optionally substituted heterocyclyl,
an optionally substituted aryl, an optionally substituted
heteroaryl, an optionally substituted aralkyl, an optionally
substituted heteraralkyl, alkoxyalkyl, guanadino,
--NR.sub.10R.sub.11 (provided R.sub.10 and R.sub.11 are not
--H)--O--R.sub.20, --SR.sub.7 (provided R.sub.7 is not H),
--S(O).sub.pR.sub.7, --OS(O).sub.pR.sub.7,
--NR.sub.8S(O).sub.pR.sub.7, --S(O).sub.pNR.sub.10R.sub.11,
--OP(O)(OR.sub.7).sub.2, --SP(O)(OR.sub.7).sub.2, --OR.sub.A,
--SR.sub.B, or --N(R.sub.C).sub.2; or
[0197] ii) two to five substituents selected from the group
consisting of an optionally substituted alkyl, an optionally
substituted alkenyl, an optionally substituted alkynyl, an
optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted heterocyclyl, an optionally
substituted aryl, an optionally substituted heteroaryl, an
optionally substituted aralkyl, an optionally substituted
heteraralkyl, alkoxyalkyl, --F, --Br, --I, cyano, nitro, guanadino,
a haloalkyl, a heteroalkyl, --NR.sub.10R.sub.11 (provided R.sub.10
and R.sub.11 are not H)--OR.sub.7--SR.sub.7, --S(O).sub.pR.sub.7,
--OS(O).sub.pR.sub.7, --NR.sub.8S(O).sub.pR.sub.7,
--S(O).sub.pNR.sub.10R.sub.11, --OP(O)(OR.sub.7).sub.2, or
--SP(O)(OR.sub.7).sub.2, --S(O).sub.pOR.sub.7, --OR.sub.A,
--SR.sub.B, or --N(R.sub.C).sub.2,
[0198] wherein R.sub.7, R.sub.8, R.sub.10, R.sub.11, R.sub.A,
R.sub.B, R.sub.C, and p are as described above for Structural
Formulas (I)-(IV).
[0199] For Structural Formulas (IA), (IA'), (IIA), and (IIIA), the
substituents for the phenyl group is selected from the group
consisting of --OR.sub.p1, --NHR.sub.p3, --N(R.sub.p3).sub.2,
--O(CH.sub.2).sub.mOR.sub.p1, or --(CH.sub.2).sub.mOR.sub.p1; an
optionally substituted alkyl, an optionally substituted alkenyl, an
optionally substituted alkynyl, an optionally substituted
cycloalkyl, an optionally substituted cycloalkenyl, an optionally
substituted heterocyclyl, an optionally substituted aryl, an
optionally substituted heteroaryl, an optionally substituted
aralkyl, an optionally substituted heteraralkyl, alkoxyalkyl,
haloalkoxyalkyl, a heteroalkyl, or a haloalkyl; halo, cyano, or
nitro; --NR.sub.10R.sub.11, or --OR.sub.7;
--O(CH.sub.2).sub.mNR.sub.7R.sub.p3; --C(O)R.sub.7, --C(O)OR.sub.7;
--C(O)NR.sub.10R.sub.11; --OC(O)R.sub.7, --OC(O)OR.sub.7,
--OC(O)NR.sub.10R.sub.11; --NR.sub.8C(O)R.sub.7, or
--NR.sub.7C(O)NR.sub.10R.sub.11; --NR.sub.7C(O)OR.sub.7;
--S(O).sub.pR.sub.7, --OS(O).sub.pR.sub.7, --OS(O).sub.pOR.sub.7,
--OS(O).sub.pNR.sub.10R.sub.11, --S(O).sub.pOR.sub.7,
--S(O).sub.pNR.sub.10R.sub.11; --NR.sub.8S(O).sub.pR.sub.7,
--NR.sub.7S(O).sub.pNR.sub.10R.sub.11,
--NR.sub.7S(O).sub.pOR.sub.7. Values and specific values for
R.sub.p1, R.sub.p3, R.sub.7, R.sub.8, R.sub.10, R.sub.11, p and m
are as defined above with reference to formulas (IA), (IA'), (IIA),
and (IIIA)
[0200] For Structural Formulas (IB), (IIIB), (VIIB), (VIIIB), (IXB)
and (XIB), the phenyl group is substituted with:
[0201] i) the one substituent selected from nitro, cyano, a
haloalkoxy, an optionally substituted alkenyl, an optionally
substituted alkynyl, an optionally substituted cycloalkyl, an
optionally substituted cycloalkenyl, an optionally substituted
heterocyclyl, an optionally substituted aryl, an optionally
substituted heteroaryl, an optionally substituted aralkyl, an
optionally substituted heteraralkyl, protected hydroxylalkyl,
alkoxyalkyl, guanadino, --OR.sub.100, --SR.sub.101,
--N(R.sub.102).sub.2, --NR.sub.10R.sub.11, --OR.sub.7, or
--C(O)R.sub.7; or
[0202] ii) two to five substituents selected from the group
consisting of an optionally substituted alkyl, an optionally
substituted alkenyl, an optionally substituted alkynyl, an
optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted heterocyclyl, an optionally
substituted aryl, an optionally substituted heteroaryl, an
optionally substituted aralkyl, an optionally substituted
heteraralkyl, protected hydroxyalkyl, alkoxyalkyl, --F, --Br, --I,
cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, --OR.sub.100,
--SR.sub.101, --N(R.sub.102).sub.2, --NR.sub.10R.sub.11,
--OR.sub.100, or --C(O)R.sub.7; and; and the values and preferred
values of the remaining variables are as described in Structural
Formulas (IB), (IIIB), (VIIB), (VIIIB), (IXB) and (XIB).
[0203] Preferably, for Structural Formulas (I)-(IV), (IA), (IA'),
(IIA), (IIIA), (IB), (IIIB), (VIIB), (VIIIB), (IXB) and (XIB),
R.sub.5 is represented by the following structural formula:
##STR00059##
[0204] R.sub.10 and R.sub.11 are as described above.
[0205] In a ninth specific embodiment, R.sub.5 in Structural
Formulas (I)-(IV), (IA), (IA'), (IIA), (IIIA), (IB), (IIIB),
(VIIB), (VIIB), (IXB) and (XIB) is selected from the group
consisting of:
##STR00060##
[0206] wherein:
[0207] X.sub.6, for each occurrence, is independently CH, CR.sub.9,
N, N(O), N.sup.+(R.sub.17), provided that at least three X.sub.6
groups are independently selected from CH and CR.sub.9;
[0208] X.sub.7, for each occurrence, is independently CH, CR.sub.9,
N, N(O), N.sup.+(R.sub.17), provided that at least three X.sub.7
groups are independently selected from CH and CR.sub.9;
[0209] X.sub.8, for each occurrence, is independently CH.sub.2,
CHR.sub.9, C(R.sub.9).sub.2, S, S(O).sub.p, NR.sub.7, or
NR.sub.17;
[0210] X.sub.9, for each occurrence, is independently N or CH;
[0211] X.sub.10, for each occurrence, is independently CH,
CR.sub.9, N, N(O), N.sup.+(R.sub.17), provided that at least one
X.sub.10 is selected from CH and CR.sub.9;
[0212] R.sub.17, for each occurrence, is independently --H, an
alkyl, an aralkyl.
[0213] For Structural Formulas (IA), (IA'), (IIA), and (IIIA),
R.sub.17 can also be --C(O)R.sub.7, --C(O)OR.sub.7 or
--C(O)NR.sub.10R.sub.11.
[0214] For Structural Formulas (IB), (IIIB), (VIIB), (VIIIB), (IXB)
and (XIB), R.sub.17 can also be --C(O)R.sub.7.
[0215] Values and specific values for the remainder of the
variables are as described above in the fifth specific
embodiment.
[0216] Preferably, for the ninth specific embodiment, R.sub.5 is an
optionally substituted indolyl, an optionally substituted
benzoimidazolyl, an optionally substituted indazolyl, an optionally
substituted 3H-indazolyl, an optionally substituted indolizinyl, an
optionally substituted quinolinyl, an optionally substituted
isoquinolinyl, an optionally substituted benzoxazolyl, an
optionally substituted benzo[1,3]dioxolyl, an optionally
substituted benzofuryl, an optionally substituted benzothiazolyl,
an optionally substituted benzo[d]isoxazolyl, an optionally
substituted benzo[d]isothiazolyl, an optionally substituted
thiazolo[4,5-c]pyridinyl, an optionally substituted
thiazolo[5,4-c]pyridinyl, an optionally substituted
thiazolo[4,5-b]pyridinyl, an optionally substituted
thiazolo[5,4-b]pyridinyl, an optionally substituted
oxazolo[4,5-c]pyridinyl, an optionally substituted
oxazolo[5,4-c]pyridinyl, an optionally substituted
oxazolo[4,5-b]pyridinyl, an optionally substituted
oxazolo[5,4-b]pyridinyl, an optionally substituted
imidazopyridinyl, an optionally substituted benzothiadiazolyl,
benzoxadiazolyl, an optionally substituted benzotriazolyl, an
optionally substituted tetrahydroindolyl, an optionally substituted
azaindolyl, an optionally substituted quinazolinyl, an optionally
substituted purinyl, an optionally substituted
imidazo[4,5-a]pyridinyl, an optionally substituted
imidazo[1,2-a]pyridinyl, an optionally substituted
3H-imidazo[4,5-b]pyridinyl, an optionally substituted
1H-imidazo[4,5-b]pyridinyl, an optionally substituted
1H-imidazo[4,5-c]pyridinyl, an optionally substituted
3H-imidazo[4,5-c]pyridinyl, an optionally substituted
pyridopyrdazinyl, and optionally substituted pyridopyrimidinyl, an
optionally substituted pyrrolo[2,3]pyrimidyl, an optionally
substituted pyrazolo[3,4]pyrimidyl an optionally substituted
cyclopentaimidazolyl, an optionally substituted
cyclopentatriazolyl, an optionally substituted pyrrolopyrazolyl, an
optionally substituted pyrroloimidazolyl, an optionally substituted
pyrrolotriazolyl, or an optionally substituted benzo[b]thienyl.
[0217] In a tenth specific embodiment, R.sub.5 in Structural
Formulas (I)-(IV), (IA), (IA'), (IIA), (IIIA), (IB), (IIIB),
(VIIB), (VIIIB), (IXB) and (XIB) is selected from the group
consisting of:
##STR00061##
[0218] wherein:
[0219] X.sub.11, for each occurrence, is independently CH,
CR.sub.9, N, N(O), or N.sup.+(R.sub.17), provided that at least one
X.sub.11 is N, N(O), or N.sup.+(R.sub.17) and at least two X.sub.11
groups are independently selected from CH and CR.sub.9;
[0220] X.sub.12, for each occurrence, is independently CH,
CR.sub.9, N, N(O), N.sup.+(R.sub.17), provided that at least one
X.sub.12 group is independently selected from CH and CR.sub.9;
[0221] X.sub.13, for each occurrence, is independently O, S,
S(O).sub.p, NR.sub.7, or NR.sub.17.
[0222] Values and specific values for the remainder of the
variables are as described in the ninth specific embodiment.
[0223] In a eleventh specific embodiment, R.sub.5 in Structural
Formulas (I)-(IV), (IA), (IA'), (IIA), (IIIA), (IB), (IIIB),
(VIIB), (VIIB), (IXB) and (XIB) is an optionally substituted
cycloalkyl, and optionally substituted cycloalkenyl, or a
substituted alkyl, wherein the alkyl group is substituted with one
or more substituents independently selected from the following
groups:
[0224] for Structural Formulas (I)-(IV), the one or more
substituents for the alkyl group are independently selected from
the group consisting of an optionally substituted alkynyl, an
optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted heteroaryl, an optionally
substituted aralkyl, an optionally substituted heteraralkyl, halo,
cyano, nitro, guanadino, a haloalkyl, --NR.sub.10R.sub.11 (provided
R.sub.10 and R.sub.11 is not H), --OR.sub.7 (provided R.sub.7 is
not H), --SR.sub.7 (provided R.sub.7 is not H),
--S(O).sub.pR.sub.7, --OS(O).sub.pR.sub.7,
--NR.sub.8S(O).sub.pR.sub.7, --S(O).sub.pNR.sub.10R.sub.11,
--OR.sub.A, --SR.sub.B, or --N(R.sub.C).sub.2, wherein values and
specific values for R.sub.7, R.sub.8, R.sub.10, R.sub.11, R.sub.A,
R.sub.B, R.sub.C, and p are as described for the Structural
Formulas (I)-(IV);
[0225] for Structural Formulas (IA), (IA'), (IIA), and (IIIA), the
one or more substituents for the alkyl or the cycloalkyl group are
independently selected from the group consisting of --OR.sub.p1,
--NHR.sub.p3, --N(R.sub.p3).sub.2, --O(CH.sub.2).sub.mOR.sub.p1, or
--(CH.sub.2).sub.mOR.sub.p1; an optionally substituted alkyl, an
optionally substituted alkenyl, an optionally substituted alkynyl,
an optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted heterocyclyl, an optionally
substituted aryl, an optionally substituted heteroaryl, an
optionally substituted aralkyl, an optionally substituted
heteraralkyl, alkoxyalkyl, haloalkoxyalkyl, a heteroalkyl, or a
haloalkyl; halo, cyano, or nitro; --NR.sub.10R.sub.11, or
--OR.sub.7; --O(CH.sub.2).sub.mNR.sub.7R.sub.p3; --C(O)R.sub.7,
--C(O)OR.sub.7; --C(O)NR.sub.10R.sub.11; --OC(O)R.sub.7,
--OC(O)OR.sub.7, --OC(O)NR.sub.10R.sub.11; --NR.sub.8C(O)R.sub.7,
or --NR.sub.7C(O)NR.sub.10R.sub.11; --NR.sub.7C(O)OR.sub.7;
--S(O).sub.pR.sub.7, --OS(O).sub.pR.sub.7, --OS(O).sub.pOR.sub.7,
--OS(O).sub.pNR.sub.10R.sub.11, --S(O).sub.pOR.sub.7,
--S(O).sub.pNR.sub.10R.sub.11; --NR.sub.8S(O).sub.pR.sub.7,
--NR.sub.7S(O).sub.pNR.sub.10R.sub.11,
--NR.sub.7S(O).sub.pOR.sub.7. Values and preferred values for
R.sub.p1, R.sub.3, R.sub.7, R.sub.8, R.sub.10, R.sub.11, p and m
are as defined above with reference to Structural Formulas (IA),
(IA'), (IIA), and (IIIA).
[0226] for Structural Formulas (IB), (IIIB), (VIIB), (VIIIB), (IXB)
and (XIB), the one or more substituents for the alkyl group are
independently selected from the group consisting of an optionally
substituted alkynyl, an optionally substituted cycloalkyl, an
optionally substituted cycloalkenyl, an optionally substituted
heteroaryl, an optionally substituted aralkyl, an optionally
substituted heteraralkyl, halo, cyano, nitro, guanadino, a
haloalkyl, --NR.sub.10R.sub.11, --OR.sub.100, and
--C(O)R.sub.7.
[0227] Values and specific values for the remainder of the
variables are as described above for Structural Formulas (I)-(IV),
(IA), (IA'), (IIA), (IIIA), (IB), (IIIB), (VIIB), (VIIB), (IXB) and
(XIB).
[0228] In a more specific embodiment, R.sub.5 in Structural
Formulas (I)-(IV), (IA), (IA'), (IIA), (IIIA), (IB), (IIIB),
(VIIB), (VIIIB), (IXB) and (XIB) is an optionally substituted
cycloalkyl or an optionally substituted cycloalkenyl. The remainder
of the variables are as described above in the eleventh specific
embodiment.
[0229] In another more specific embodiment, R.sub.5 in Structural
Formulas (I)-(IV), (IA), (IA'), (IIA), (IIIA), (IB), (IIIB),
(VIIB), (VIIIB), (IXB) and (XIB), is a substituted alkyl. The
remainder of the variables are as described above in the eleventh
specific embodiment.
[0230] In a twelfth specific embodiment, ring A in Structural
Formulas (I)-(IV), (IA), (IA'), (IIA), (IVA), (IB), (IIIB), (VIIB),
(VIIIB), (IXB), and (XIB) is presented by Structural Formula
(IX):
##STR00062##
[0231] wherein: [0232] For Structural Formulas (I)-(IV), R.sub.300
is R.sub.3 as described in Structural Formulas (I)-(IV). R.sub.6,
for each occurrence, is independently an optionally substituted
alkyl, an optionally substituted alkenyl, an optionally substituted
alkynyl, an optionally substituted cycloalkyl, an optionally
substituted cycloalkenyl, an optionally substituted heterocyclyl,
an optionally substituted aryl, an optionally substituted
heteroaryl, an optionally substituted aralkyl, an optionally
substituted heteroaralkyl, halo, cyano, nitro, guanadino, a
haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, --NR.sub.10R.sub.11
(provided R.sub.10 and R.sub.11 are not --H), --OR.sub.7 (provided
R.sub.7 is not H), --C(NR.sub.8)OR.sub.7,
--C(NR.sub.8)NR.sub.10R.sub.11, --C(NR.sub.8)SR.sub.7,
--OC(S)OR.sub.7, --OC(NR.sub.8)OR.sub.7,
--SC(NR.sub.8)OR.sub.7--SC(S)OR.sub.7, --OC(S)NR.sub.10R.sub.11,
--OC(NR.sub.8)NR.sub.10R.sub.11, --SC(NR.sub.8)NR.sub.10R.sub.11,
--SC(S)NR.sub.10R.sub.11, --OC(NR.sub.8)R.sub.7,
--SC(NR.sub.8)R.sub.7, --NR.sub.7C(S)OR.sub.7,
--NR.sub.7C(NR.sub.8)R.sub.7, --NR.sub.7C(NR.sub.8)OR.sub.7,
--NR.sub.7C(S)NR.sub.10R.sub.11,
--NR.sub.7C(NR.sub.8)NR.sub.10R.sub.11, --SR.sub.7 (provided
R.sub.7 is not H), --S(O).sub.pR.sub.7, --OS(O).sub.pR.sub.7,
--OS(O).sub.pNR.sub.10R.sub.11, --S(O).sub.pOR.sub.7,
--NR.sub.8S(O).sub.pR.sub.7, --NR.sub.7S(O).sub.pNR.sub.10R.sub.11,
--NR.sub.7S(O).sub.pOR.sub.7, --S(O).sub.pNR.sub.10R.sub.11,
--SS(O).sub.pR.sub.7, --SS(O).sub.pOR.sub.7,
--SS(O).sub.pNR.sub.10R.sub.11, --OP(O)(OR.sub.7).sub.2, or
--SP(O)(OR.sub.7).sub.2, --OR.sub.A, --SR.sub.B, or
--N(R.sub.C).sub.2; [0233] For Structural Formulas (IA), (IA'),
(IIA) and (IVA), R.sub.300 is R.sub.20 as described in Structural
Formulas (IA), (IA'), (IIA) and (IVA). R.sub.6, for each
occurrence, is independently a substituent selected from:
--OR.sub.p1, --NHR.sub.p3, --N(R.sub.p3).sub.2,
--O(CH.sub.2).sub.mOR.sub.p1, or --(CH.sub.2).sub.mOR.sub.p1; an
optionally substituted alkyl, an optionally substituted alkenyl, an
optionally substituted alkynyl, an optionally substituted
cycloalkyl, an optionally substituted cycloalkenyl, an optionally
substituted heterocyclyl, an optionally substituted aryl, an
optionally substituted heteroaryl, an optionally substituted
aralkyl, an optionally substituted heteraralkyl, alkoxyalkyl,
haloalkoxyalkyl, a heteroalkyl, or a haloalkyl; halo, cyano, or
nitro; --NR.sub.10R.sub.11, or --OR.sub.7;
--O(CH.sub.2).sub.mNR.sub.7R.sub.p3; --C(O)R.sub.7, --C(O)OR.sub.7;
--C(O)NR.sub.10R.sub.11; --OC(O)R.sub.7, --OC(O)OR.sub.7,
--OC(O)NR.sub.10R.sub.11; --NR.sub.8C(O)R.sub.7, or
--NR.sub.7C(O)NR.sub.10R.sub.11; --NR.sub.7C(O)OR.sub.7;
--S(O).sub.pR.sub.7, --OS(O).sub.pR.sub.7, --OS(O).sub.pOR.sub.7,
--OS(O).sub.pNR.sub.10R.sub.11, --S(O).sub.pOR.sub.7,
--S(O).sub.pNR.sub.10R.sub.11; --NR.sub.8S(O).sub.pR.sub.7,
--NR.sub.7S(O).sub.pNR.sub.10R.sub.11,
--NR.sub.7S(O).sub.pOR.sub.7; [0234] For Structural Formulas (IB),
(IIIB), (VIIB), (VIIIB), (IXB), and (XIB), R.sub.300 is R.sub.3b as
described above in Structural Formulas (IB), (IIIB), (VIIB),
(VIIIB), (IXB), and (XIB). R.sub.6, for each occurrence, is
independently an optionally substituted alkyl, an optionally
substituted alkenyl, an optionally substituted alkynyl, an
optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted heterocyclyl, an optionally
substituted aryl, an optionally substituted heteroaryl, an
optionally substituted aralkyl, an optionally substituted
heteroaralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a
heteroalkyl, alkoxy, a protected hydroxyalkyl, haloalkoxy,
--NR.sub.10R.sub.11, --OR.sub.100, --C(O)R.sub.7, or --SR.sub.101;
or two R.sub.6 groups, taken together with the carbon atoms to
which they are attached, form a fused ring; [0235] For Structural
Formulas (I)-(IV), (IA), (IA'), (IIA), (IVA), (IB), (IIIB), (VIIB),
(VIIIB), (IXB), and (XIB), n is zero or an integer from 1 to 4. The
remainder of the variables are as described above in Structural
Formulas (I)-(IV), (IA), (IA'), (IIA), (IVA), (IVA), (IB), (IIIB),
(VIIB), (VIIIB), (IXB), and (XIB).
[0236] In a more specific embodiment, R.sub.5 in compounds of
Structural Formulas (I)-(IV), (IA), (IA'), (IIA), (IB), (IIIB),
(VIIB), (VIIIB), (IXB), and (XIB) is an optionally substituted
phenyl, wherein the phenyl group is substituted with substituents
as described in the eighth specific embodiment. Values and specific
values for the remainder of the variables are as described in the
twelfth specific embodiment. Preferably, for Structural Formulas
(I)-(IV), R.sub.3 is --OR.sub.A, SR.sub.B, N(R.sub.C).sub.2.
[0237] In another more specific embodiment, R.sub.5 in compounds of
Structural Formulas (I)-(IV), (IA), (IA'), (IIA), (IB), (IIIB),
(VIIB), (VIIIB), (IXB), and (XIB), is an optionally substituted
cycloalkyl, and optionally substituted cycloalkenyl, or a
substituted alkyl, wherein the alkyl group is substituted with one
or more substituents independently selected from the group
described above in the eleventh specific embodiment. Values and
specific values for the remainder of the variables are as described
in the twelfth specific embodiment. In a even more specific
embodiment, R.sub.5 is an optionally substituted cycloalkyl or an
optionally substituted cycloalkenyl. In another even more specific
embodiment, R.sub.5 is an optionally substituted alkyl.
[0238] In another more specific embodiment, R.sub.5 in the
compounds of Structural Formulas (I)-(IV), (IA), (IA'), (IIA),
(IB), (IIIB), (VIIB), (VIIIB), (IXB), and (XIB) is represented by
the following structural formula:
##STR00063##
[0239] wherein R.sub.9 and m are as described in the fifth specific
embodiment. Values and specific values for the remainder of the
variables are as described the twelfth specific embodiment.
[0240] In another more specific embodiment, R.sub.5 in compounds of
Structural Formulas (I)-(IV), (IA), (IA'), (IIA), (IB), (IIIB),
(VIIB), (VIIIB), (IXB), and (XIB), is selected from the group
consisting of the following structural formulas:
##STR00064##
wherein X.sub.6, X.sub.7, X.sub.8, X.sub.9, X.sub.10 and R.sub.17
are as described in the ninth specific embodiment. Values and
specific values for the remainder of the variables are as described
in the twelfth specific embodiment. Preferably, R.sub.5 is an
optionally substituted indolyl, an optionally substituted
benzoimidazolyl, an optionally substituted indazolyl, an optionally
substituted 3H-indazolyl, an optionally substituted indolizinyl, an
optionally substituted quinolinyl, an optionally substituted
isoquinolinyl, an optionally substituted benzoxazolyl, an
optionally substituted benzo[1,3]dioxolyl, an optionally
substituted benzofuryl, an optionally substituted benzothiazolyl,
an optionally substituted benzo[d]isoxazolyl, an optionally
substituted benzo[d]isothiazolyl, an optionally substituted
thiazolo[4,5-c]pyridinyl, an optionally substituted
thiazolo[5,4-c]pyridinyl, an optionally substituted
thiazolo[4,5-b]pyridinyl, an optionally substituted
thiazolo[5,4-b]pyridinyl, an optionally substituted
oxazolo[4,5-c]pyridinyl, an optionally substituted
oxazolo[5,4-c]pyridinyl, an optionally substituted
oxazolo[4,5-b]pyridinyl, an optionally substituted
oxazolo[5,4-b]pyridinyl, an optionally substituted
imidazopyridinyl, an optionally substituted benzothiadiazolyl,
benzoxadiazolyl, an optionally substituted benzotriazolyl, an
optionally substituted tetrahydroindolyl, an optionally substituted
azaindolyl, an optionally substituted quinazolinyl, an optionally
substituted purinyl, an optionally substituted
imidazo[4,5-a]pyridinyl, an optionally substituted
imidazo[1,2-a]pyridinyl, an optionally substituted
3H-imidazo[4,5-b]pyridinyl, an optionally substituted
1H-imidazo[4,5-b]pyridinyl, an optionally substituted
1H-imidazo[4,5-c]pyridinyl, an optionally substituted
3H-imidazo[4,5-c]pyridinyl, an optionally substituted
pyridopyrdazinyl, and optionally substituted pyridopyrimidinyl, an
optionally substituted pyrrolo[2,3]pyrimidyl, an optionally
substituted pyrazolo[3,4]pyrimidyl an optionally substituted
cyclopentaimidazolyl, an optionally substituted
cyclopentatriazolyl, an optionally substituted pyrrolopyrazolyl, an
optionally substituted pyrroloimidazolyl, an optionally substituted
pyrrolotriazolyl, or an optionally substituted benzo[b]thienyl.
[0241] In another more specific embodiment, R.sub.5 in the
compounds of Structural Formulas (I)-(IV), (IA), (IA'), (IIA),
(IB), (IIIB), (VIIB), (VIIIB), (IXB), and (XIB), is selected from
the group consisting of the following structural formulas:
##STR00065##
[0242] wherein X.sub.11, X.sub.12, X.sub.13, R.sub.9 and R.sub.17
are defined as described in the tenth specific embodiment. Values
and specific values for the remainder of the variables are as
described in the twelfth specific embodiment.
[0243] In another more specific embodiment, R.sub.5 in the
compounds of Structural Formulas (I)-(IV), (IA), (IA'), (IIA),
(IB), (IIIB), (VIIB), (VIIIB), (IXB), and (XIB) is an optionally
substituted indolyl. Preferably, R.sub.5 is an indolyl represented
by the following Structural Formula:
##STR00066##
[0244] wherein R.sub.33, R.sub.34, ring B and ring C are as
described above in the seventh specific embodiment. Values and
specific values for the remainder of the variables are as described
above in the twelfth specific embodiment.
[0245] In the thirteenth specific embodiment, ring A in compounds
represented by Structural Formulas (I)-(IV), (IA), (IA'), (IIA),
(IVA), (IB), (IIIB), (VIIB), (VIIIB), (IXB), and (XIB) is
represented by the Structural Formula (X):
##STR00067##
[0246] wherein: [0247] for Structural Formulas (I)-(IV), R.sub.25
is an optionally substituted alkyl, an optionally substituted
alkenyl, an optionally substituted alkynyl, an optionally
substituted cycloalkyl, an optionally substituted cycloalkenyl, an
optionally substituted heterocyclyl, an optionally substituted
aryl, an optionally substituted heteroaryl, an optionally
substituted aralkyl, an optionally substituted heteroaralkyl, halo,
cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy,
haloalkoxy, or --NR.sub.10R.sub.11 (provided R.sub.10 and R.sub.11
are not H); [0248] for Structural Formulas (IA), (IA'), (IIA), and
(IVA), R.sub.25 is --OR.sub.p1, --NHR.sub.p3, --N(R.sub.p3).sub.2,
--O(CH.sub.2).sub.mOR.sub.p1, or --(CH.sub.2).sub.mOR.sub.p1; an
optionally substituted alkyl, an optionally substituted alkenyl, an
optionally substituted alkynyl, an optionally substituted
cycloalkyl, an optionally substituted cycloalkenyl, an optionally
substituted heterocyclyl, an optionally substituted aryl, an
optionally substituted heteroaryl, an optionally substituted
aralkyl, an optionally substituted heteraralkyl, alkoxyalkyl,
haloalkoxyalkyl, a heteroalkyl, or a haloalkyl; halo, cyano, or
nitro; --NR.sub.10R.sub.11, or --OR.sub.7;
--O(CH.sub.2).sub.mNR.sub.7R.sub.p3; --C(O)R.sub.7, --C(O)OR.sub.7;
--C(O)NR.sub.10R.sub.11; --OC(O)R.sub.7, --OC(O)OR.sub.7,
--OC(O)NR.sub.10R.sub.11; --NR.sub.8C(O)R.sub.7, or
--NR.sub.7C(O)NR.sub.10R.sub.11; --NR.sub.7C(O)OR.sub.7;
--S(O).sub.pR.sub.7, --OS(O).sub.pR.sub.7, --OS(O).sub.pOR.sub.7,
--OS(O).sub.pNR.sub.10R.sub.11, --S(O).sub.pOR.sub.7,
--S(O).sub.pNR.sub.10R.sub.11; --NR.sub.8S(O).sub.pR.sub.7,
--NR.sub.7S(O).sub.pNR.sub.10R.sub.11, or
--NR.sub.7S(O).sub.pOR.sub.7; [0249] for Structural Formulas (IB),
(IIIB), (VIIB), (VIIIB), (IXB), and (XIB), R.sub.25 is a
substituent selected from the group consisting of an optionally
substituted alkyl, an optionally substituted alkenyl, an optionally
substituted alkynyl, an optionally substituted cycloalkyl, an
optionally substituted cycloalkenyl, an optionally substituted
heterocyclyl, an optionally substituted aryl, an optionally
substituted heteroaryl, an optionally substituted aralkyl, an
optionally substituted heteraralkyl, protected hydroxyalkyl,
alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, a
heteroalkyl, --NR.sub.10R.sub.11, --OR.sub.100, and --C(O)R.sub.7;
[0250] r for Structural Formulas (I)-(IV), (IA), (IA'), (IIA),
(IVA), (IB), (IIIB), (VIIB), (VIIIB), (IXB), and (XIB) is zero or
an integer from 1 to 3.
[0251] Values and specific values for the remainder of the
variables are as described above in the twelfth specific
embodiment.
[0252] In a more specific embodiment, R.sub.25 in Structural
Formulas (I)-(IV) is --OR.sub.A, --SR.sub.B, --N(R.sub.C).sub.2,
--OC(S)OR.sub.7, --OC(NR.sub.8)OR.sub.7, --SC(NR.sub.8)OR.sub.7,
--SC(S)OR.sub.7, --OC(S)NR.sub.10R.sub.11,
--SC(S)NR.sub.10R.sub.11, --OC(NR.sub.8)R.sub.7,
--SC(NR.sub.8)R.sub.7, --OS(O).sub.pR.sub.7, --S(O).sub.pOR.sub.7,
--SS(O).sub.pOR.sub.7, --SS(O).sub.pR.sub.7,
--OP(O)(OR.sub.7).sub.2, or --SP(O)(OR.sub.7).sub.2, wherein p is
0, 1, or 2; Values and specific values for the remainder of the
variables are as described in the thirteenth specific
embodiment.
[0253] In another more specific embodiment, R.sub.25 in Structural
Formulas (IA), (IA'), (IIA), and (IVA) is a --OR.sub.p1,
--NHR.sub.p3, --N(R.sub.p3).sub.2, --O(CH.sub.2).sub.mOR.sub.p1, or
--(CH.sub.2).sub.mOR.sub.p1.
[0254] In another more specific embodiment, R.sub.33 is H,
--OR.sub.p1, --NHR.sub.p3, --N(R.sub.p3).sub.2,
--O(CH.sub.2).sub.mOR.sub.p1, or --(CH.sub.2).sub.mOR.sub.p1; and
R.sub.34 is a C.sub.1-C.sub.6 alkyl.
[0255] In another more specific embodiment, R.sub.3b and R.sub.25
in Structural Formulas (IB), (IIIB), (VIIB), (VIIIB), (IXB), and
(XIB) are --OR.sub.100, --SR.sub.101, or --N(R.sub.102).sub.2. Even
more specifically, R.sub.1b is --SH or --OH; R.sub.3b and R.sub.25
are --OR.sub.100; and R.sub.51 is .dbd.O or .dbd.S. Even more
specifically, R.sub.1b is --SH or --OH; R.sub.3b and R.sub.25 are
--OR.sub.100; R.sub.51 is .dbd.O or .dbd.S; and R.sub.6 is an
optionally substituted lower alkyl, a C3-C6 cycloalkyl, a lower
alkoxy, a lower alkyl sulfanyl, or --NR.sub.10R.sub.11.
[0256] In another more specific embodiment, R.sub.5 in Structural
Formulas (I)-(IV), (IA), (IA'), (IIA), (IB), (IIIB), (VIIB),
(VIIIB), (IXB), and (XIB) is an optionally substituted phenyl,
wherein the phenyl group is substituted with substituents as
described in the eighth specific embodiment. Values and specific
values for the remainder of the variables are as described in the
thirteenth specific embodiment. Preferably, R.sub.3 is --OR.sub.A,
SR.sub.B, N(R.sub.C).sub.2.
[0257] In another more specific embodiment, R.sub.5 in compounds of
Structural Formulas (I)-(IV), (IA), (IA'), (IIA), (IB), (IIIB),
(VIIB), (VIIIB), (IXB), and (XIB), is an optionally substituted
cycloalkyl, and optionally substituted cycloalkenyl, or a
substituted alkyl, wherein the alkyl group is substituted with one
or more substituents independently selected from the group as
described above in the eleventh specific embodiment. The remainder
of the variables are as described in the thirteenth specific
embodiment. In a even more specific embodiment, R.sub.5 is an
optionally substituted cycloalkyl or an optionally substituted
cycloalkenyl. In another even more specific embodiment, R.sub.5 is
an optionally substituted alkyl.
[0258] In another more specific embodiment, R.sub.5 in the
compounds of Structural Formulas (I)-(IV), (IA), (IA'), (IIA),
(IB), (IIIB), (VIIB), (VIIIB), (IXB), and (XIB) is represented by
the following structural formula:
##STR00068##
[0259] wherein R.sub.9 and m are as described in the fifth specific
embodiment. Values and specific values for the remainder of the
variables are as described the thirteenth specific embodiment.
[0260] In another more specific embodiment, R.sub.5 in compounds of
Structural Formulas (I)-(IV), (IA), (IA'), (IIA), (IB), (IIIB),
(VIIB), (VIIIB), (IXB), and (XIB), is selected from the group
consisting of the following structural formulas:
##STR00069##
wherein X.sub.6, X.sub.7, X.sub.8, X.sub.9, X.sub.10 and R.sub.17
are as described in the ninth specific embodiment. The remainder of
the variables are as described in the thirteenth specific
embodiment. Preferably, R.sub.5 is an optionally substituted
indolyl, an optionally substituted benzoimidazolyl, an optionally
substituted indazolyl, an optionally substituted 3H-indazolyl, an
optionally substituted indolizinyl, an optionally substituted
quinolinyl, an optionally substituted isoquinolinyl, an optionally
substituted benzoxazolyl, an optionally substituted
benzo[1,3]dioxolyl, an optionally substituted benzofuryl, an
optionally substituted benzothiazolyl, an optionally substituted
benzo[d]isoxazolyl, an optionally substituted benzo[d]isothiazolyl,
an optionally substituted thiazolo[4,5-c]pyridinyl, an optionally
substituted thiazolo[5,4-c]pyridinyl, an optionally substituted
thiazolo[4,5-b]pyridinyl, an optionally substituted
thiazolo[5,4-b]pyridinyl, an optionally substituted
oxazolo[4,5-c]pyridinyl, an optionally substituted
oxazolo[5,4-c]pyridinyl, an optionally substituted
oxazolo[4,5-b]pyridinyl, an optionally substituted
oxazolo[5,4-b]pyridinyl, an optionally substituted
imidazopyridinyl, an optionally substituted benzothiadiazolyl,
benzoxadiazolyl, an optionally substituted benzotriazolyl, an
optionally substituted tetrahydroindolyl, an optionally substituted
azaindolyl, an optionally substituted quinazolinyl, an optionally
substituted purinyl, an optionally substituted
imidazo[4,5-a]pyridinyl, an optionally substituted
imidazo[1,2-a]pyridinyl, an optionally substituted
3H-imidazo[4,5-b]pyridinyl, an optionally substituted
1H-imidazo[4,5-b]pyridinyl, an optionally substituted
1H-imidazo[4,5-c]pyridinyl, an optionally substituted
3H-imidazo[4,5-c]pyridinyl, an optionally substituted
pyridopyrdazinyl, and optionally substituted pyridopyrimidinyl, an
optionally substituted pyrrolo[2,3]pyrimidyl, an optionally
substituted pyrazolo[3,4]pyrimidyl an optionally substituted
cyclopentaimidazolyl, an optionally substituted
cyclopentatriazolyl, an optionally substituted pyrrolopyrazolyl, an
optionally substituted pyrroloimidazolyl, an optionally substituted
pyrrolotriazolyl, or an optionally substituted benzo[b]thienyl.
[0261] In another more specific embodiment, R.sub.5 in Structural
Formulas (I)-(IV), (IA), (IA'), (IIA), (IB), (IIIB), (VIIB),
(VIIIB), (IXB), and (XIB) is an optionally substituted indolyl.
Preferably, R.sub.5 is an indolyl represented by the following
Structural Formula:
##STR00070##
[0262] wherein R.sub.33, R.sub.34, ring B and ring C are as
described above in the seventh specific embodiment. Values and
specific values for the remainder of the variables are as described
above in the thirteenth specific embodiment. In a even more
specific embodiment, for Structural Formulas (IA), (IA') and (IIA),
R.sub.25 is a --OR.sub.p1, --NHR.sub.p3, --N(R.sub.p3).sub.2,
--O(CH.sub.2).sub.mOR.sub.p1, or --(CH.sub.2).sub.mOR.sub.p1. In
another even more specific embodiment, for Structural Formulas
(IA), (IA') and (IIA), R.sub.33 is H, --OR.sub.p1, --NHR.sub.p3,
--N(R.sub.p3).sub.2, --O(CH.sub.2).sub.mOR.sub.p1, or
--(CH.sub.2).sub.mOR.sub.p1 and R.sub.34 is a C.sub.1-C.sub.6
alkyl. In another even more specific embodiment, for Structural
Formulas (IA), (IA') and (IIA), R.sub.25 is a --OR.sub.p1,
--NHR.sub.p3, --N(R.sub.p3).sub.2, --O(CH.sub.2).sub.mOR.sub.p1, or
--(CH.sub.2).sub.mOR.sub.p1; R.sub.33 is H, --OR.sub.p1,
--NHR.sub.p3, --N(R.sub.p3).sub.2, --O(CH.sub.2).sub.mOR.sub.p1, or
(CH.sub.2).sub.mOR.sub.p1 and R.sub.34 is a C1-C6 alkyl. In a even
more specific embodiment, for Structural Formulas (IA), (IA') and
(IIA), R.sub.21 is O; R.sub.6 is a C1-C6 alkyl, a C1-C6 haloalkyl,
a C1-C6 alkoxy, a C1-C6 haloalkoxy, a C3-C6 cycloalkyl or
--NR.sub.10R.sub.11. In another even more specific embodiment, for
Structural Formulas (IA), (IA') and (IIA), R.sub.6 is a C1-C6 alkyl
and R.sub.33 is H. In another even more specific embodiment, for
Structural Formulas (IA), (IA') and (IIA), R.sub.33 is --H and ring
B is unsubstituted. In another even more specific embodiment, for
Structural Formulas (IA), (IA') and (IIA), R.sub.20 and R.sub.25
are --OH, and R.sub.6 is a C1-C6 alkyl. In another even more
specific embodiment, for Structural Formula (IA), (IA') and (IIA),
R.sub.21 is O; R.sub.6 is a C1-C6 alkyl and R.sub.33 is H. In
another even more specific embodiment, for Structural Formulas
(IA), (IA') and (IIA), R.sub.21 is O; R.sub.6 is a C.sub.1-C.sub.6
alkyl; R.sub.33 is H and ring B is unsubstituted. In yet another
even more embodiment, for Structural Formula (IA), (IA') and (IIA),
R.sub.21 is O; R.sub.6 is a C1-C6 alkyl; R.sub.33 is H; ring B is
unsubstituted; R.sub.20 and R.sub.25 are --OH, and R.sub.6 is a
C1-C6 alkyl.
[0263] In another more specific embodiment, R.sub.5 in the
compounds of Structural Formulas (I)-(IV), (IA), (IA'), (IIA),
(IB), (IIIB), (VIIB), (VIIIB), (IXB), and (XIB), is selected from
the group consisting of the following structural formulas:
##STR00071##
[0264] wherein X.sub.11, X.sub.12, X.sub.13, R.sub.9 and R.sub.17
are defined as described in the tenth specific embodiment. Values
and specific values for the remainder of the variables are as
described in the thirteenth specific embodiment.
[0265] In a fourteenth specific embodiment, ring A of the compounds
of Structural Formulas (I)-(IV), (IA), (IA'), (IIA), (IVA), (IB),
(IIIB), (VIIB), (VIIIB), (IXB), and (XIB), is represented by
Structural Formula (XI):
##STR00072##
[0266] wherein R.sub.1, R.sub.300, R.sub.5, R.sub.6, and R.sub.25
are defined as the thirteenth specific embodiment. More
specifically, R.sub.25 in Structural Formulas (I)-(IV) is
--OR.sub.A, --SR.sub.B, --N(R.sub.C).sub.2, --OC(S)OR.sub.7,
--OC(NR.sub.8)OR.sub.7, --SC(NR.sub.8)OR.sub.7, --SC(S)OR.sub.7,
--OC(S)NR.sub.10R.sub.11, --SC(S)NR.sub.10R.sub.11,
--OC(NR.sub.8)R.sub.7, --SC(NR.sub.8)R.sub.7, --OS(O).sub.pR.sub.7,
--S(O).sub.pOR.sub.7, --SS(O).sub.pOR.sub.7, --SS(O).sub.pR.sub.7,
--OP(O)(OR.sub.7).sub.2, or --SP(O)(OR.sub.7).sub.2, wherein p is
0, 1, or 2. In a more specific embodiment, for Structural Formulas
(I)-(IV), R.sub.3 and R.sub.25 are --OR.sub.A. Even more
specifically, R.sub.6 is a lower alkyl, C.sub.3-C.sub.6 cycloalkyl,
lower alkoxy, a lower alkyl sulfanyl, or --NR.sub.10R.sub.11.
[0267] In a more specific embodiment, for Structural Formulas
(IA'), (IIA) and (IVA), R.sub.21 is O; R.sub.6 is a C1-C6 alkyl, a
C1-C6 haloalkyl, a C1-C6 alkoxy, a C1-C6 haloalkoxy, a C3-C6
cycloalkyl or --NR.sub.10R.sub.11. In another more specific
embodiment, for Structural Formulas (IA'), (IIA) and (IVA), R.sub.6
is a C1-C6 alkyl and R.sub.33 is H. In another more specific
embodiment, for Structural Formulas (IA'), (IIA) and (IVA),
R.sub.33 is --H and ring B is unsubstituted. In yet another more
specific embodiment, for Structural Formulas (IA'), (IIA) and
(IVA), R.sub.20 and R.sub.25 are --OH, and R.sub.6 is a C1-C6
alkyl.
[0268] In another more specific embodiment, for Structural Formulas
(IB), (IIIB), (VIIB), (VIIIB), (IXB), and (XIB), R.sub.3b and
R.sub.25 are --OR.sub.100, --SR.sub.101, or
--N(R.sub.102).sub.2.
[0269] In another more specific embodiment, for Structural Formulas
(IB), (IIIB), (VIIB), (VIIIB), (IXB), and (XIB), R.sub.1 is --SH,
R.sub.3 and R.sub.25 are --OR.sub.100; and R.sub.51 is .dbd.O or
.dbd.S.
[0270] In another more specific embodiment, for Structural Formulas
(IB), (IIIB), (VIIB), (VIIIB), (IXB), and (XIB), R.sub.1b is --SH
or --OH; R.sub.3b and R.sub.25 are --OR.sub.100; R.sub.51 is .dbd.O
or .dbd.S; and R.sub.6 is an optionally substituted lower alkyl, a
C3-C6 cycloalkyl, a lower alkoxy, a lower alkyl sulfanyl, or
--NR.sub.10R.sub.11.
[0271] In another more specific embodiment, R.sub.5 in Structural
Formulas (I)-(IV), (IA), (IA'), (IIA), (IB), (IIIB), (VIIB),
(VIIIB), (IXB), and (XIB), is an optionally substituted phenyl,
wherein the phenyl group is substituted with substituents as
described above in the eighth specific embodiment. Values and
specific values for the remainder of the variables are as described
above in the fourteenth specific embodiment. Even more
specifically, for Structural Formulas (I)-(IV), R.sub.3 and
R.sub.25 are --OR.sub.A. Even more specifically, for Structural
Formulas (I)-(IV), R.sub.3 and R.sub.25 are --OR.sub.A; R.sub.6 is
a lower alkyl, C3-C6 cycloalkyl, a lower alkoxy, a lower alkyl
sulfanyl, or --NR.sub.10R.sub.11.
[0272] In another more specific embodiment, R.sub.5 in the
compounds of Structural Formulas (I)-(IV), (IA), (IA'), (IIA),
(IB), (IIIB), (VIIB), (VIIIB), (IXB), and (XIB), is represented by
the following structural formula:
##STR00073##
and values and specific values for the remainder of the variables
are as described in the fourteenth specific embodiment. Preferably,
R.sub.10 and R.sub.11 are each independently a hydrogen, a C1-C6
straight or branched alkyl, optionally substituted by --OR.sub.A,
--CN, --SR.sub.A, --N(R.sub.C).sub.2, a C1-C6 alkoxy,
alkylsulfanyl, dialkylamino or a cycloalkyl; or R.sub.10 and
R.sub.11 taken together with the nitrogen to which they are
attached form a substituted or unsubstituted nonaromatic,
nitrogen-containing heterocyclyl. More preferably, R.sub.10 and
R.sub.11 are each independently a hydrogen, methyl, ethyl, propyl,
isopropyl, or taken together with the nitrogen to which they are
attached, are:
##STR00074##
[0273] In another more specific embodiment, R.sub.5 in compounds of
Structural Formulas (I)-(IV), (IA), (IA'), (IIA), (IB), (IIIB),
(VIIB), (VIIIB), (IXB), and (XIB), is an optionally substituted
cycloalkyl, and optionally substituted cycloalkenyl, or a
substituted alkyl, wherein the alkyl group is substituted with one
or more substituents independently selected from the group
described above in the eleventh specific embodiment. Values and
specific values for the remainder of the variables are as described
in the fourteenth specific embodiment. In a even more specific
embodiment, R.sub.5 is an optionally substituted cycloalkyl or an
optionally substituted cycloalkenyl. In another even more specific
embodiment, R.sub.5 is an optionally substituted alkyl.
[0274] In another more specific embodiment, R.sub.5 in the
compounds of Structural Formulas (I)-(IV), (IA), (IA'), (IIA),
(IB), (IIIB), (VIIB), (VIIIB), (IXB), and (XIB) is represented by
the following structural formula:
##STR00075##
[0275] wherein R.sub.9 and m are as described in the fifth specific
embodiment. Values and specific values for the remainder of the
variables are as described the fourteenth specific embodiment. In a
even more specific embodiment, for Structural Formulas (I)-(IV),
R.sub.3 and R.sub.25 are --OR.sub.A; R.sub.6 is a lower alkyl, a
C3-C6 cycloalkyl, a lower alkoxy, a lower alkyl sulfanyl, or
--NR.sub.10R.sub.11; and R.sub.9 for each occurrence, is
independently selected from the group consisting of --OR.sub.A,
--SR.sub.B, halo, a lower haloalkyl, cyano, a lower alkyl, a lower
alkoxy, and a lower alkyl sulfanyl.
[0276] In another more specific embodiment, R.sub.5 in compounds of
Structural Formulas (I)-(IV), (IA), (IA'), (IIA), (IB), (IIIB),
(VIIB), (VIIIB), (IXB), and (XIB), is selected from the group
consisting of the following structural formulas:
##STR00076##
wherein X.sub.6, X.sub.7, X.sub.8, X.sub.9, X.sub.10 and R.sub.17
are as described in the ninth specific embodiment. The remainder of
the variables are as described in the fourteenth specific
embodiment. Preferably, R.sub.5 is an optionally substituted
indolyl, an optionally substituted benzoimidazolyl, an optionally
substituted indazolyl, an optionally substituted 3H-indazolyl, an
optionally substituted indolizinyl, an optionally substituted
quinolinyl, an optionally substituted isoquinolinyl, an optionally
substituted benzoxazolyl, an optionally substituted
benzo[1,3]dioxolyl, an optionally substituted benzofuryl, an
optionally substituted benzothiazolyl, an optionally substituted
benzo[d]isoxazolyl, an optionally substituted benzo[d]isothiazolyl,
an optionally substituted thiazolo[4,5-c]pyridinyl, an optionally
substituted thiazolo[5,4-c]pyridinyl, an optionally substituted
thiazolo[4,5-b]pyridinyl, an optionally substituted
thiazolo[5,4-b]pyridinyl, an optionally substituted
oxazolo[4,5-c]pyridinyl, an optionally substituted
oxazolo[5,4-c]pyridinyl, an optionally substituted
oxazolo[4,5-b]pyridinyl, an optionally substituted
oxazolo[5,4-b]pyridinyl, an optionally substituted
imidazopyridinyl, an optionally substituted benzothiadiazolyl,
benzoxadiazolyl, an optionally substituted benzotriazolyl, an
optionally substituted tetrahydroindolyl, an optionally substituted
azaindolyl, an optionally substituted quinazolinyl, an optionally
substituted purinyl, an optionally substituted
imidazo[4,5-a]pyridinyl, an optionally substituted
imidazo[1,2-a]pyridinyl, an optionally substituted
3H-imidazo[4,5-b]pyridinyl, an optionally substituted
1H-imidazo[4,5-b]pyridinyl, an optionally substituted
1H-imidazo[4,5-c]pyridinyl, an optionally substituted
3H-imidazo[4,5-c]pyridinyl, an optionally substituted
pyridopyrdazinyl, and optionally substituted pyridopyrimidinyl, an
optionally substituted pyrrolo[2,3]pyrimidyl, an optionally
substituted pyrazolo[3,4]pyrimidyl an optionally substituted
cyclopentaimidazolyl, an optionally substituted
cyclopentatriazolyl, an optionally substituted pyrrolopyrazolyl, an
optionally substituted pyrroloimidazolyl, an optionally substituted
pyrrolotriazolyl, or an optionally substituted benzo[b]thienyl. In
a even more specific embodiment, R.sub.6 is a lower alkyl, a C3-C6
cycloalkyl, a lower alkoxy, a lower alkyl sulfanyl, or
--NR.sub.10R.sub.11. In another even more specific embodiment,
R.sub.6 is a lower alkyl, a C3-C6 cycloalkyl, a lower alkoxy, a
lower alkyl sulfanyl, or --NR.sub.10R.sub.11; and R.sub.3 and
R.sub.25 are --OR.sub.A.
[0277] In another more specific embodiment, R.sub.5 is represented
by the following Structural Formula:
##STR00077##
wherein values and specific values for the variables are as
described below in the eighteenth specific embodiment. In a even
more specific embodiment, R.sub.6 is selected from the group
consisting of --H, a lower alkyl, a lower alkoxy, a lower
cycloalkyl, and a lower cycloalkoxy.
[0278] In another more specific embodiment, R.sub.5 in the
compounds of Structural Formulas (I)-(IV), (IA), (IA'), (IIA),
(IB), (IIIB), (VIIB), (VIIIB), (IXB), and (XIB), is selected from
the group consisting of the following structural formulas:
##STR00078##
[0279] wherein X.sub.11, X.sub.12, X.sub.13, R.sub.9 and R.sub.17
are defined as described in the tenth specific embodiment. The
remainder of the variables are as described in the fourteenth
specific embodiment. In a even more specific embodiment, R.sub.6 is
a lower alkyl, a C3-C6 cycloalkyl, a lower alkoxy, a lower alkyl
sulfanyl, or --NR.sub.10R.sub.11. In another even more specific
embodiment, R.sub.6 is a lower alkyl, a C3-C6 cycloalkyl, a lower
alkoxy, a lower alkyl sulfanyl, or --NR.sub.10R.sub.11; and R.sub.3
and R.sub.25 are --OR.sub.A.
[0280] In another more specific embodiment, R.sub.5 in Structural
Formulas (I)-(IV), (IA), (IA'), (IIA), (IB), (IIIB), (VIIB),
(VIIIB), (IXB), and (XIB) is an optionally substituted indolyl.
Preferably, R.sub.5 is an indolyl represented by the following
Structural Formula:
##STR00079##
[0281] wherein R.sub.33, R.sub.34, ring B and ring C are as
described above in the seventh specific embodiment. Values and
specific values for the remainder of the variables are as described
above in the thirteenth specific embodiment. In a even more
specific embodiment, for Structural Formulas (IA), (IA') and (IIA),
R.sub.25 is a --OR.sub.p1, --NHR.sub.p3, --N(R.sub.p3).sub.2,
--O(CH.sub.2).sub.mOR.sub.p1, or --(CH.sub.2).sub.mOR.sub.p1;
R.sub.33 is H, --OR.sub.p1, --NHR.sub.p3, --N(R.sub.p3).sub.2,
--O(CH.sub.2).sub.mOR.sub.p1, or --(CH.sub.2).sub.mOR.sub.p1; and
R.sub.34 is a C.sub.1-C.sub.6 alkyl. In another more specific
embodiment, for Structural Formulas (IA), (IA') and (IIA), R.sub.21
is O; R.sub.6 is a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy,
a C1-C6 haloalkoxy, a C3-C6 cycloalkyl or --NR.sub.10R.sub.11. In
another even more specific embodiment, for Structural Formulas
(IA), (IA') and (IIA), R.sub.6 is a C1-C6 alkyl and R.sub.33 is H.
In another even more specific embodiment, for Structural Formulas
(IA), (IA') and (IIA), R.sub.33 is --H and ring B is unsubstituted.
In another even more specific embodiment, for Structural Formulas
(IA), (IA') and (IIA), R.sub.6 is a C1-C6 alkyl; R.sub.33 is H; and
ring B is unsubstituted. In yet another even more embodiment, In
another even more specific embodiment, for Structural Formulas
(IA), (IA') and (IIA), R.sub.20 and R.sub.25 are --OH, and R.sub.6
is a C1-C6 alkyl.
[0282] In a fifteenth specific embodiment, ring A in compounds of
Structural Formulas (I)-(IV), (IA), (IA'), (IIA), (IVA), (IB),
(IIIB), (VIIB), (VIIIB), (IXB), and (XIB), is represented by one of
Structural Formulas (XII):
##STR00080##
[0283] X.sub.3 and X.sub.4 are each, independently, N, N(O),
N.sup.+(R.sub.17), CH or CR.sub.6; and
[0284] X.sub.5 is O, S, NR.sub.17, CH.dbd.CH, CH.dbd.CR.sub.6,
CR.sub.6.dbd.CH, CR.sub.6.dbd.CR.sub.6, CH.dbd.N, CR.sub.6.dbd.N,
CH.dbd.N(O), CR.sub.6.dbd.N(O), N.dbd.CH, N.dbd.CR.sub.6,
N(O).dbd.CH, N(O).dbd.CR.sub.6, N.sup.+(R.sub.17).dbd.CH,
N.sup.+(R.sub.17).dbd.CR.sub.6, CH.dbd.N.sup.+(R.sub.17),
CR.sub.6.dbd.N.sup.+(R.sub.17), or N.dbd.N; wherein R.sub.17 is
defined as in the ninth specific embodiment. Values and specific
values for the remainder of the variables is as described in the
twelfth specific embodiment.
[0285] In a more specific embodiment, R.sub.5 in the compounds of
Structural Formulas (I)-(IV), (IA), (IA'), (IIA), (IB), (IIIB),
(VIIB), (VIIIB), (IXB), and (XIB), is an optionally substituted
phenyl, wherein the phenyl group is substituted with substituents
as described in the eighth specific embodiment. The remainder of
the variables are as described in the fifteenth specific
embodiment. More specifically, for Structural Formulas (I)-(IV),
R.sub.3 and R.sub.25 are --OR.sub.A. Even more specifically,
R.sub.6 is a lower alkyl, C.sub.3-C.sub.6 cycloalkyl, lower alkoxy,
a lower alkyl sulfanyl, or --NR.sub.10R.sub.11.
[0286] In another more specific embodiment, R.sub.5 in compounds of
Structural Formulas (I)-(IV), (IA), (IA'), (IIA), (IB), (IIIB),
(VIIB), (VIIIB), (IXB), and (XIB), is an optionally substituted
cycloalkyl, and optionally substituted cycloalkenyl, or a
substituted alkyl, wherein the alkyl group is substituted with one
or more substituents independently selected from the group
described above in the eleventh specific embodiment. The remainder
of the variables are as described in the fifteenth specific
embodiment. In a more specific embodiment, R.sub.5 is an optionally
substituted cycloalkyl or an optionally substituted cycloalkenyl.
In another more specific embodiment, R.sub.5 is an optionally
substituted alkyl.
[0287] In another more specific embodiment, R.sub.5 in the
compounds of Structural Formulas (I)-(IV), (IA), (IA'), (IIA),
(IB), (IIIB), (VIIB), (VIIIB), (IXB), and (XIB) is represented by
the following structural formula:
##STR00081##
[0288] wherein R.sub.9 and m are as described in the fifth specific
embodiment. Values and specific values for the remainder of the
variables are as described the fifteenth specific embodiment.
[0289] In another more specific embodiment, R.sub.5 in compounds of
Structural Formulas (I)-(IV), (IA), (IA'), (IIA), (IB), (IIIB),
(VIIB), (VIIIB), (IXB), and (XIB), is selected from the group
consisting of the following structural formulas:
##STR00082##
wherein X.sub.6, X.sub.7, X.sub.8, X.sub.9, X.sub.10 and R.sub.17
are as described in the ninth specific embodiment. Values and
specific values for the remainder of the variables are as described
above in the fifteenth specific embodiment. Preferably, R.sub.5 is
an optionally substituted indolyl, an optionally substituted
benzoimidazolyl, an optionally substituted indazolyl, an optionally
substituted 3H-indazolyl, an optionally substituted indolizinyl, an
optionally substituted quinolinyl, an optionally substituted
isoquinolinyl, an optionally substituted benzoxazolyl, an
optionally substituted benzo[1,3]dioxolyl, an optionally
substituted benzofuryl, an optionally substituted benzothiazolyl,
an optionally substituted benzo[d]isoxazolyl, an optionally
substituted benzo[d]isothiazolyl, an optionally substituted
thiazolo[4,5-c]pyridinyl, an optionally substituted
thiazolo[5,4-c]pyridinyl, an optionally substituted
thiazolo[4,5-b]pyridinyl, an optionally substituted
thiazolo[5,4-b]pyridinyl, an optionally substituted
oxazolo[4,5-c]pyridinyl, an optionally substituted
oxazolo[5,4-c]pyridinyl, an optionally substituted
oxazolo[4,5-b]pyridinyl, an optionally substituted
oxazolo[5,4-b]pyridinyl, an optionally substituted
imidazopyridinyl, an optionally substituted benzothiadiazolyl,
benzoxadiazolyl, an optionally substituted benzotriazolyl, an
optionally substituted tetrahydroindolyl, an optionally substituted
azaindolyl, an optionally substituted quinazolinyl, an optionally
substituted purinyl, an optionally substituted
imidazo[4,5-a]pyridinyl, an optionally substituted
imidazo[1,2-a]pyridinyl, an optionally substituted
3H-imidazo[4,5-b]pyridinyl, an optionally substituted
1H-imidazo[4,5-b]pyridinyl, an optionally substituted
1H-imidazo[4,5-c]pyridinyl, an optionally substituted
3H-imidazo[4,5-c]pyridinyl, an optionally substituted
pyridopyrdazinyl, and optionally substituted pyridopyrimidinyl, an
optionally substituted pyrrolo[2,3]pyrimidyl, an optionally
substituted pyrazolo[3,4]pyrimidyl an optionally substituted
cyclopentaimidazolyl, an optionally substituted
cyclopentatriazolyl, an optionally substituted pyrrolopyrazolyl, an
optionally substituted pyrroloimidazolyl, an optionally substituted
pyrrolotriazolyl, or an optionally substituted benzo[b]thienyl.
[0290] In another more specific embodiment, R.sub.5 in the
compounds of Structural Formulas (I)-(IV), (IA), (IA'), (IIA),
(IB), (IIIB), (VIIB), (VIIIB), (IXB), and (XIB), is selected from
the group consisting of the following structural formulas:
##STR00083##
[0291] wherein X.sub.11, X.sub.12, X.sub.13, R.sub.9 and R.sub.17
are defined as described in the tenth specific embodiment. Values
and specific values for the remainder of the variables are as
described in the fifteenth specific embodiment.
[0292] In another more specific embodiment, R.sub.5 in Structural
Formulas (I)-(IV), (IA), (IA'), (IIA), (IB), (IIIB), (VIIB),
(VIIIB), (IXB), and (XIB) is an optionally substituted indolyl.
Preferably, R.sub.5 is an indolyl represented by the following
Structural Formula:
##STR00084##
[0293] wherein R.sub.33, R.sub.34, ring B and ring C are as
described above in the seventh specific embodiment. Values and
specific values for the remainder of the variables are as described
above in the thirteenth specific embodiment. In a even more
specific embodiment, for Structural Formulas (XIIA), R.sub.21 is O;
R.sub.6 is a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, a
C1-C6 haloalkoxy, a C3-C6 cycloalkyl or --NR.sub.10R.sub.11. In
another even more specific embodiment, for Structural Formula
(XIIA), R.sub.6 is a C1-C6 alkyl and R.sub.33 is H. In another even
more specific embodiment, for Structural Formula (XIIA), R.sub.33
is --H and ring B is unsubstituted. In yet another even more
embodiment, for Structural Formula (XIIA), R.sub.20 and R.sub.25
are --OH, and R.sub.6 is a C1-C6 alkyl.
[0294] In a sixteenth specific embodiment, ring A in compounds
represented by Structural Formulas (I)-(IV), (IA), (IA'), (IIA),
(IVA), (IB), (IIIB), (VIIB), (VIIB), (IXB), and (XIB), is selected
from Structural Formula (XIII):
##STR00085##
[0295] wherein R.sub.1, R.sub.300, R.sub.5, and R.sub.25 are as
described above in the thirteenth specific embodiment.
Specifically, for Structural Formulas (IB), (IIIB), (VIIB),
(VIIIB), (IXB), and (XIB), R.sub.25 is a halo, a haloalkyl, a
haloalkoxy, a heteroalkyl, --OR.sub.100, --SR.sub.101,
--N(R.sub.102).sub.2, --NR.sub.7R.sub.102, --OR.sub.26,
--SR.sub.26, --NR.sub.26R.sub.102, --O(CH.sub.2).sub.mOH,
--O(CH.sub.2).sub.mSH, --O(CH.sub.2).sub.mNR.sub.7H,
--S(CH.sub.2).sub.mOH, --S(CH.sub.2).sub.mSH,
--S(CH.sub.2).sub.mNR.sub.7H, --OCH.sub.2C(O)R.sub.7,
--SCH.sub.2C(O)R.sub.7, and --NR.sub.7CH.sub.2C(O)R.sub.7. k is 1,
2, 3, or 4. The values and specific values of the remaining
variables are as described above in the fifteenth specific
embodiment.
[0296] In a more specific embodiment, R.sub.5 in the compounds of
Structural Formulas (I)-(IV), (IA), (IA'), (IIA), (IB), (IIIB),
(VIIB), (VIIIB), (IXB), and (XIB), is an optionally substituted
phenyl, wherein the phenyl group is substituted with substituents
as described in the eighth specific embodiment. Values and specific
values for the remainder of the variables are as described in the
sixteenth specific embodiment. Even more specifically, for
Structural Formulas (I)-(IV), R.sub.3 and R.sub.25 are --OR.sub.A.
Even more specifically, R.sub.6 is a lower alkyl, C3-C6 cycloalkyl,
lower alkoxy, a lower alkyl sulfanyl, or --NR.sub.10R.sub.11.
[0297] In another more specific embodiment, R.sub.5 in compounds of
Structural Formulas (I)-(IV), (IA), (IA'), (IIA), (IB), (IIIB),
(VIIB), (VIIIB), (IXB), and (XIB), is an optionally substituted
cycloalkyl, and optionally substituted cycloalkenyl, or a
substituted alkyl, wherein the alkyl group is substituted with one
or more substituents independently selected from the group
described above in the eleventh specific embodiment. Values and
specific values for the remainder of the variables are as described
in the sixteenth specific embodiment. In a more specific
embodiment, R.sub.5 is an optionally substituted cycloalkyl or an
optionally substituted cycloalkenyl. In another more specific
embodiment, R.sub.5 is an optionally substituted alkyl.
[0298] In another more specific embodiment, R.sub.5 in the
compounds of Structural Formulas (I)-(IV), (IA), (IA'), (IIA),
(IB), (IIIB), (VIIB), (VIIIB), (IXB), and (XIB) is represented by
the following structural formula:
##STR00086##
[0299] wherein R.sub.9 and m are as described in the fifth specific
embodiment. The remainder of the variables are as described the
sixteenth specific embodiment.
[0300] In another more specific embodiment, R.sub.5 in compounds of
Structural Formulas (I)-(IV), (IA), (IA'), (IIA), (IB), (IIIB),
(VIIB), (VIIIB), (IXB), and (XIB), is selected from the group
consisting of the following structural formulas:
##STR00087##
wherein X.sub.6, X.sub.7, X.sub.8, X.sub.9, X.sub.10 and R.sub.17
are as described in the ninth specific embodiment. Values and
specific values for the remainder of the variables are as described
in the sixteenth specific embodiment. Preferably, R.sub.5 is an
optionally substituted indolyl, an optionally substituted
benzoimidazolyl, an optionally substituted indazolyl, an optionally
substituted 3H-indazolyl, an optionally substituted indolizinyl, an
optionally substituted quinolinyl, an optionally substituted
isoquinolinyl, an optionally substituted benzoxazolyl, an
optionally substituted benzo[1,3]dioxolyl, an optionally
substituted benzofuryl, an optionally substituted benzothiazolyl,
an optionally substituted benzo[d]isoxazolyl, an optionally
substituted benzo[d]isothiazolyl, an optionally substituted
thiazolo[4,5-c]pyridinyl, an optionally substituted
thiazolo[5,4-c]pyridinyl, an optionally substituted
thiazolo[4,5-b]pyridinyl, an optionally substituted
thiazolo[5,4-b]pyridinyl, an optionally substituted
oxazolo[4,5-c]pyridinyl, an optionally substituted
oxazolo[5,4-c]pyridinyl, an optionally substituted
oxazolo[4,5-b]pyridinyl, an optionally substituted
oxazolo[5,4-b]pyridinyl, an optionally substituted
imidazopyridinyl, an optionally substituted benzothiadiazolyl,
benzoxadiazolyl, an optionally substituted benzotriazolyl, an
optionally substituted tetrahydroindolyl, an optionally substituted
azaindolyl, an optionally substituted quinazolinyl, an optionally
substituted purinyl, an optionally substituted
imidazo[4,5-a]pyridinyl, an optionally substituted
imidazo[1,2-a]pyridinyl, an optionally substituted
3H-imidazo[4,5-b]pyridinyl, an optionally substituted
1H-imidazo[4,5-b]pyridinyl, an optionally substituted
1H-imidazo[4,5-c]pyridinyl, an optionally substituted
3H-imidazo[4,5-c]pyridinyl, an optionally substituted
pyridopyrdazinyl, and optionally substituted pyridopyrimidinyl, an
optionally substituted pyrrolo[2,3]pyrimidyl, an optionally
substituted pyrazolo[3,4]pyrimidyl an optionally substituted
cyclopentaimidazolyl, an optionally substituted
cyclopentatriazolyl, an optionally substituted pyrrolopyrazolyl, an
optionally substituted pyrroloimidazolyl, an optionally substituted
pyrrolotriazolyl, or an optionally substituted benzo[b]thienyl.
[0301] In another more specific embodiment, R.sub.5 in the
compounds of Structural Formulas (I)-(IV), (IA), (IA'), (IIA),
(IB), (IIIB), (VIIB), (VIIIB), (IXB), and (XIB), is selected from
the group consisting of the following structural formulas:
##STR00088##
[0302] wherein X.sub.11, X.sub.12, X.sub.13, R.sub.9 and R.sub.17
are defined as described in the tenth specific embodiment. Values
and specific values for the remainder of the variables are as
described in the sixteenth specific embodiment.
[0303] In another more specific embodiment, R.sub.5 in Structural
Formulas (I)-(IV), (IA), (IA'), (IIA), (IB), (IIIB), (VIIB),
(VIIIB), (IXB), and (XIB) is an optionally substituted indolyl.
Preferably, R.sub.5 is an indolyl represented by the following
Structural Formula:
##STR00089##
[0304] wherein R.sub.33, R.sub.34, ring B and ring C are as
described above in the seventh specific embodiment. Values and
specific values for the remainder of the variables are as described
above in the thirteenth specific embodiment. In a even more
specific embodiment, for Structural Formulas (XIIA), R.sub.21 is O;
R.sub.6 is a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, a
C1-C6 haloalkoxy, a C3-C6 cycloalkyl or --NR.sub.10R.sub.11. In
another even more specific embodiment, for Structural Formula
(XIIA), R.sub.6 is a C1-C6 alkyl and R.sub.33 is H. In another even
more specific embodiment, for Structural Formula (XIIA), R.sub.33
is --H and ring B is unsubstituted. In yet another even more
embodiment, for Structural Formula (XIIA), R.sub.20 and R.sub.25
are --OH, and R.sub.6 is a C1-C6 alkyl.
[0305] In a seventeenth specific embodiment, compounds of
Structural Formulas (I)-(IV), (IA), (IA'), (IIA), (IB), (IIIB),
(VIIB), (VIIIB), (IXB), and (XIB) are defined as the following:
[0306] R.sub.5 is an optionally substituted alkyl, an optionally
substituted alkenyl, an optionally substituted alkynyl, an
optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted heterocyclyl, an optionally
substituted aryl, an optionally substituted heteroaryl, an
optionally substituted aralkyl, or an optionally substituted
heteraralkyl;
[0307] ring A is represented by Structural Formulas (XIV):
##STR00090##
[0308] wherein,
[0309] X.sub.14 is O, S, or NR.sub.7;
[0310] for Structural Formulas (I)-(IV):
[0311] R.sub.22, for each occurrence, is independently an --H or is
selected from the group consisting of an optionally substituted
alkyl, an optionally substituted alkenyl, an optionally substituted
alkynyl, an optionally substituted cycloalkyl, an optionally
substituted cycloalkenyl, an optionally substituted heterocyclyl,
an optionally substituted aryl, an optionally substituted
heteroaryl, an optionally substituted aralkyl, or an optionally
substituted heteraralkyl, a haloalkyl, --S(O).sub.pR.sub.7, or
--S(O).sub.pNR.sub.10R.sub.11; and
[0312] R.sub.23 and R.sub.24, for each occurrence, are
independently --H or are selected from the group consisting of an
optionally substituted alkyl, an optionally substituted alkenyl, an
optionally substituted alkynyl, an optionally substituted
cycloalkyl, an optionally substituted cycloalkenyl, an optionally
substituted heterocyclyl, an optionally substituted aryl, an
optionally substituted heteroaryl, an optionally substituted
aralkyl, or an optionally substituted heteraralkyl, halo, cyano,
nitro, guanadino, a haloalkyl, a heteroalkyl, --NR.sub.10R.sub.11
(provided R.sub.10 and R.sub.11 are not H), --OR.sub.7 (provided
R.sub.7 is not H), --SR.sub.7 (provided R.sub.7 is not H),
--S(O).sub.pR.sub.7, --OS(O).sub.pR.sub.7,
--NR.sub.8S(O).sub.pR.sub.7, or --S(O).sub.pNR.sub.10R.sub.11;
[0313] for Structural Formulas (IA), (IA') and (IIA):
[0314] R.sub.22, for each occurrence, is independently an --H or is
selected from the group consisting of an optionally substituted
alkyl, an optionally substituted alkenyl, an optionally substituted
alkynyl, an optionally substituted cycloalkyl, an optionally
substituted cycloalkenyl, an optionally substituted heterocyclyl,
an optionally substituted aryl, an optionally substituted
heteroaryl, an optionally substituted aralkyl, or an optionally
substituted heteraralkyl, a haloalkyl, --C(O)R.sub.7,
--C(O)OR.sub.7, --OC(O)R.sub.7, --C(O)NR.sub.10R.sub.11,
--NR.sub.8C(O)R.sub.7, --S(O).sub.pR.sub.7, --S(O).sub.pOR.sub.7 or
--S(O).sub.pNR.sub.10R.sub.11; and
[0315] R.sub.23 and R.sub.24, for each occurrence, are
independently --H or are selected from the group consisting of an
optionally substituted alkyl, an optionally substituted alkenyl, an
optionally substituted alkynyl, an optionally substituted
cycloalkyl, an optionally substituted cycloalkenyl, an optionally
substituted heterocyclyl, an optionally substituted aryl, an
optionally substituted heteroaryl, an optionally substituted
aralkyl, or an optionally substituted heteraralkyl, halo, cyano,
nitro, guanadino, a haloalkyl, a heteroalkyl, --NR.sub.10R.sub.11,
--OR.sub.7, --C(O)R.sub.7, --C(O)OR.sub.7, --OC(O)R.sub.7,
--C(O)NR.sub.10R.sub.11, --NR.sub.8C(O)R.sub.7, --SR.sub.7,
--S(O).sub.pR.sub.7, --OS(O).sub.pR.sub.7,
--NR.sub.8S(O).sub.pR.sub.7, or --S(O).sub.pNR.sub.10R.sub.11;
[0316] for Structural Formulas (IB), (IIIB), (VIIB), (VIIIB),
(IXB), and (XIB):
[0317] R.sub.22, for each occurrence, is independently an --H or is
selected from the group consisting of an optionally substituted
alkyl, an optionally substituted alkenyl, an optionally substituted
alkynyl, an optionally substituted cycloalkyl, an optionally
substituted cycloalkenyl, an optionally substituted heterocyclyl,
an optionally substituted aryl, an optionally substituted
heteroaryl, an optionally substituted aralkyl, or an optionally
substituted heteraralkyl, a haloalkyl, or --C(O)R.sub.7;
[0318] R.sub.23 and R.sub.24, for each occurrence, are
independently --H or are selected from the group consisting of an
optionally substituted alkyl, an optionally substituted alkenyl, an
optionally substituted alkynyl, an optionally substituted
cycloalkyl, an optionally substituted cycloalkenyl, an optionally
substituted heterocyclyl, an optionally substituted aryl, an
optionally substituted heteroaryl, an optionally substituted
aralkyl, or an optionally substituted heteraralkyl, halo, cyano,
nitro, guanadino, a haloalkyl, a heteroalkyl, --NR.sub.10R.sub.11,
--OR.sub.7, or --C(O)R.sub.7;
[0319] Values and specific values for the remainder of the
variables are as described in Structural Formulas (I)-(IV), (IA),
(IA'), (IIA), (IB), (IIIB), (VIIB), (VIIIB), (IXB), and (XIB).
[0320] In a more specific embodiment, R.sub.5 is an optionally
substituted alkyl, an optionally substituted cycloalkyl, an
optionally substituted aryl or an optionally substituted
heteroaryl. The remainder of the variables are as described in the
seventeenth specific embodiment.
[0321] In another more specific embodiment, R.sub.22 is --H, or an
alkyl, an aralkyl. The remainder of the variables are as described
in the seventeenth specific embodiment.
[0322] In another more specific embodiment, X.sub.14 is O. The
remainder of the variables are as described in the seventeenth
specific embodiment.
[0323] In a eighteenth specific embodiment, the compounds of
Structural Formulas (I)-(IV), (IA), (IA'), (IIA), (IB), (IIIB),
(VIIB), (VIIIB), (IXB), and (XIB) are defined as the following or
tautomers, pharmaceutically acceptable salts, solvates,
clarthrates, or prodrugs thereof:
[0324] Ring A is represented by the following Structural
Formula:
##STR00091##
[0325] R.sub.5 is represented by the following Structural
Formula:
##STR00092##
wherein:
[0326] X.sub.41 is O, S, or NR.sub.42;
[0327] X.sub.42 is CR.sub.44 or N;
[0328] Y.sub.40 is N or CR.sub.43;
[0329] Y.sub.41 is N or CR.sub.45;
[0330] Y.sub.42, for each occurrence, is independently N, C or
CR.sub.46;
[0331] R.sub.41, R.sub.42, R.sub.43, R.sub.44, R.sub.45, R.sub.46,
and R.sub.400 are defined as the following:
[0332] for Structural Formulas (I)-(IV), R.sub.41 is --H,
--OR.sub.A, --SR.sub.B, an optionally substituted alkyl, an
optionally substituted alkenyl, an optionally substituted alkynyl,
an optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted heterocyclyl, an optionally
substituted aryl, an optionally substituted heteroaryl, an
optionally substituted aralkyl, an optionally substituted
heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a
heteroalkyl, an alkoxy or cycloalkoxy, a haloalkoxy,
--NR.sub.10R.sub.11 (provided R.sub.10 and R.sub.11 are not H),
--OR.sub.7 (provided R.sub.7 is not H), --C(NR.sub.8)OR.sub.7,
--C(NR.sub.8)R.sub.7, --C(NR.sub.8)NR.sub.10R.sub.11,
--C(NR.sub.8)SR.sub.7, --OC(S)OR.sub.7, --OC(NR.sub.8)OR.sub.7,
--SC(NR.sub.8)OR.sub.7, --SC(S)OR.sub.7, --OC(S)NR.sub.10R.sub.11,
--OC(NR.sub.8)NR.sub.10R.sub.11, --SC(NR.sub.8)NR.sub.10R.sub.11,
--SC(S)NR.sub.10R.sub.11, --OC(NR.sub.8)R.sub.7,
--SC(NR.sub.8)R.sub.7, --NR.sub.7C(S)OR.sub.7,
--NR.sub.7C(NR.sub.8)R.sub.7, --NR.sub.7C(NR.sub.9)OR.sub.7,
--NR.sub.7C(S)NR.sub.10R.sub.11,
--NR.sub.7C(NR.sub.8)NR.sub.10R.sub.11, --SR.sub.7 (provided
R.sub.7 is not H), --S(O).sub.pR.sub.7, --OS(O).sub.pR.sub.7,
--OS(O).sub.pNR.sub.10R.sub.11, --S(O).sub.pOR.sub.7,
--NR.sub.8S(O).sub.pR.sub.7, --NR.sub.7S(O).sub.pNR.sub.10R.sub.11,
--NR.sub.7S(O).sub.pOR.sub.7, --S(O).sub.pNR.sub.10R.sub.11,
--SS(O).sub.pR.sub.7, --SS(O).sub.pOR.sub.7,
--SS(O).sub.pNR.sub.10R.sub.11, --OP(O)(OR.sub.7).sub.2, or
--SP(O)(OR.sub.7).sub.2;
[0333] R.sub.42 is --H, an optionally substituted alkyl, an
optionally substituted alkenyl, an optionally substituted alkynyl,
an optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted heterocyclyl, an optionally
substituted aryl, an optionally substituted heteroaryl, an
optionally substituted aralkyl, an optionally substituted
heteraralkyl, alkoxyalkyl, a haloalkyl, a heteroalkyl,
--S(O).sub.pR.sub.7, or --S(O).sub.pNR.sub.10R.sub.11;
[0334] R.sub.43 and R.sub.44 are, independently, --H, --OR.sub.A,
an optionally substituted alkyl, an optionally substituted alkenyl,
an optionally substituted alkynyl, an optionally substituted
cycloalkyl, an optionally substituted cycloalkenyl, an optionally
substituted heterocyclyl, an optionally substituted aryl, an
optionally substituted heteroaryl, an optionally substituted
aralkyl, an optionally substituted heteraralkyl, alkoxyalkyl, halo,
cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, --SR.sub.7
(provided R.sub.7 is not H), --S(O).sub.pR.sub.7,
--OS(O).sub.pR.sub.7, --NR.sub.8S(O).sub.pR.sub.7,
--S(O).sub.pNR.sub.10R.sub.11, or R.sub.43 and R.sub.44 taken
together with the carbon atoms to which they are attached form an
optionally substituted cycloalkenyl, an optionally substituted
aryl, an optionally substituted heterocyclyl, or an optionally
substituted heteroaryl;
[0335] R.sub.45 is --H, --OR.sub.A, --SR.sub.B, --N(R.sub.C).sub.2,
--OR.sub.26, --SR.sub.26, --O(CH.sub.2).sub.mOR.sub.A,
--O(CH.sub.2).sub.mSR.sub.B, --O(CH.sub.2).sub.mNR.sub.7R.sub.C,
--S(CH.sub.2).sub.mOR.sub.A, --S(CH.sub.2).sub.mSR.sub.B,
--S(CH.sub.2).sub.mNR.sub.7R.sub.C, --OS(O).sub.pR.sub.7,
--SS(O).sub.pR.sub.7, --NR.sub.7S(O).sub.pR.sub.7,
--OS(O).sub.pNR.sub.10R.sub.11, --SS(O).sub.pNR.sub.10R.sub.11,
--NR.sub.7S(O).sub.pNR.sub.10R.sub.11, --SS(O).sub.pOR.sub.7,
--NR.sub.7S(O).sub.pOR.sub.7, --OC(S)OR.sub.7, --SC(S)OR.sub.7,
--NR.sub.7C(S)OR.sub.7, --OC(S)NR.sub.10R.sub.11,
--SC(S)NR.sub.10R.sub.11, --NR.sub.7C(S)NR.sub.10R.sub.11,
--OC(NR.sub.8)R.sub.7, --SC(NR.sub.8)R.sub.7,
--NR.sub.7C(NR.sub.8)R.sub.7, --OC(NR.sub.8)OR.sub.7,
--SC(NR.sub.8)OR.sub.7, --NR.sub.7C(NR.sub.8)OR.sub.7,
--OC(NR.sub.8)NR.sub.10R.sub.11, --SC(NR.sub.8)NR.sub.10R.sub.11,
or --NR.sub.7C(NR.sub.8)NR.sub.10R.sub.11;
[0336] R.sub.46, for each occurrence, is independently, selected
from the group consisting of H, an optionally substituted alkyl, an
optionally substituted alkenyl, an optionally substituted alkynyl,
an optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted heterocyclyl, an optionally
substituted aryl, an optionally substituted heteroaryl, an
optionally substituted aralkyl, an optionally substituted
heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a
heteroalkyl, --NR.sub.10R.sub.11 (provided R.sub.10 and R.sub.11
are not H), --OR.sub.7 (provided R.sub.7 is not H), --SR.sub.7
(provided R.sub.7 is not H), --S(O).sub.pR.sub.7,
--OS(O).sub.pR.sub.7, --NR.sub.8S(O).sub.pR.sub.7, or
--S(O).sub.pNR.sub.10R.sub.11;
[0337] R.sub.400 is R.sub.A as described for Structural Formulas
(I)-(IV).
[0338] for Structural Formulas (IA), (IA') and (IIA), R.sub.41 is
--H, --OR.sub.p1, --NHR.sub.p3, --N(R.sub.p3).sub.2,
--O(CH.sub.2).sub.mOR.sub.p1, or --(CH.sub.2).sub.mOR.sub.p1; an
optionally substituted alkyl, an optionally substituted alkenyl, an
optionally substituted alkynyl, an optionally substituted
cycloalkyl, an optionally substituted cycloalkenyl, an optionally
substituted heterocyclyl, an optionally substituted aryl, an
optionally substituted heteroaryl, an optionally substituted
aralkyl, an optionally substituted heteraralkyl, alkoxyalkyl,
haloalkoxyalkyl, a heteroalkyl, or a haloalkyl; halo, cyano, or
nitro; --NR.sub.10R.sub.11, or --OR.sub.7;
--O(CH.sub.2).sub.mNR.sub.7R.sub.p3; --C(O)R.sub.7, --C(O)OR.sub.7;
--C(O)NR.sub.10R.sub.11; --OC(O)R.sub.7, --OC(O)OR.sub.7,
--OC(O)NR.sub.10R.sub.11; --NR.sub.8C(O)R.sub.7, or
--NR.sub.7C(O)NR.sub.10R.sub.11; --NR.sub.7C(O)OR.sub.7;
--S(O).sub.pR.sub.7, --OS(O).sub.pR.sub.7, --OS(O).sub.pOR.sub.7,
--OS(O).sub.pNR.sub.10R.sub.11, --S(O).sub.pOR.sub.7,
--S(O).sub.pNR.sub.10R.sub.11; --NR.sub.8S(O).sub.pR.sub.7,
--NR.sub.7S(O).sub.pNR.sub.10R.sub.11,
--NR.sub.7S(O).sub.pOR.sub.7;
[0339] R.sub.42 is --H, --OR.sub.p1, --NHR.sub.p3,
--N(R.sub.p3).sub.2, --O(CH.sub.2).sub.mOR.sub.p1, or
--(CH.sub.2).sub.mOR.sub.p1; an optionally substituted alkyl, an
optionally substituted alkenyl, an optionally substituted alkynyl,
an optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted heterocyclyl, an optionally
substituted aryl, an optionally substituted heteroaryl, an
optionally substituted aralkyl, an optionally substituted
heteraralkyl, alkoxyalkyl, haloalkoxyalkyl, a heteroalkyl, or a
haloalkyl; halo, cyano, or nitro; --NR.sub.10R.sub.11, or
--OR.sub.7; --O(CH.sub.2).sub.mNR.sub.7R.sub.p3; --C(O)R.sub.7,
--C(O)OR.sub.7; --C(O)NR.sub.10R.sub.11; --OC(O)R.sub.7,
--OC(O)OR.sub.7, --OC(O)NR.sub.10R.sub.11; --NR.sub.8C(O)R.sub.7,
or --NR.sub.7C(O)NR.sub.10R.sub.11; --NR.sub.7C(O)OR.sub.7;
--S(O).sub.pR.sub.7, --OS(O).sub.pR.sub.7, --OS(O).sub.pOR.sub.7,
--OS(O).sub.pNR.sub.10R.sub.11, --S(O).sub.pOR.sub.7,
--S(O).sub.pNR.sub.10R.sub.11; --NR.sub.8S(O).sub.pR.sub.7,
--NR.sub.7S(O).sub.pNR.sub.10R.sub.11,
--NR.sub.7S(O).sub.pOR.sub.7;
[0340] R.sub.43 and R.sub.44 are, independently, --H, --OR.sub.p1,
--NHR.sub.p3, --N(R.sub.p3).sub.2, --O(CH.sub.2).sub.mOR.sub.p1, or
--(CH.sub.2).sub.mOR.sub.p1; an optionally substituted alkyl, an
optionally substituted alkenyl, an optionally substituted alkynyl,
an optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted heterocyclyl, an optionally
substituted aryl, an optionally substituted heteroaryl, an
optionally substituted aralkyl, an optionally substituted
heteraralkyl, alkoxyalkyl, haloalkoxyalkyl, a heteroalkyl, or a
haloalkyl; halo, cyano, or nitro; --NR.sub.10R.sub.11, or
--OR.sub.7; --O(CH.sub.2).sub.mNR.sub.7R.sub.p3; --C(O)R.sub.7,
--C(O)OR.sub.7; --C(O)NR.sub.10R.sub.11; --OC(O)R.sub.7,
--OC(O)OR.sub.7, --OC(O)NR.sub.10R.sub.11; --NR.sub.8C(O)R.sub.7,
or --NR.sub.7C(O)NR.sub.10R.sub.11; --NR.sub.7C(O)OR.sub.7;
--S(O).sub.pR.sub.7, --OS(O).sub.pR.sub.7, --OS(O).sub.pOR.sub.7,
--OS(O).sub.pNR.sub.10R.sub.11, --S(O).sub.pOR.sub.7,
--S(O).sub.pNR.sub.10R.sub.11; --NR.sub.8S(O).sub.pR.sub.7,
--NR.sub.7S(O).sub.pNR.sub.10R.sub.11,
--NR.sub.7S(O).sub.pOR.sub.7;
[0341] or R.sub.43 and R.sub.44 taken together with the carbon
atoms to which they are attached form an optionally substituted
cycloalkenyl, an optionally substituted aryl, an optionally
substituted heterocyclyl, or an optionally substituted
heteroaryl;
[0342] R.sub.45 is --H, --OR.sub.p1, --NHR.sub.p3,
--N(R.sub.p3).sub.2, --O(CH.sub.2).sub.mOR.sub.p1, or
--(CH.sub.2).sub.mOR.sub.p1; an optionally substituted alkyl, an
optionally substituted alkenyl, an optionally substituted alkynyl,
an optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted heterocyclyl, an optionally
substituted aryl, an optionally substituted heteroaryl, an
optionally substituted aralkyl, an optionally substituted
heteraralkyl, alkoxyalkyl, haloalkoxyalkyl, a heteroalkyl, or a
haloalkyl; halo, cyano, or nitro; --NR.sub.10R.sub.11, or
--OR.sub.7; --O(CH.sub.2).sub.mNR.sub.7R.sub.p3; --C(O)R.sub.7,
--C(O)OR.sub.7; --C(O)NR.sub.10R.sub.11; --OC(O)R.sub.7,
--OC(O)OR.sub.7, --OC(O)NR.sub.10R.sub.11; --NR.sub.8C(O)R.sub.7,
or --NR.sub.7C(O)NR.sub.10R.sub.11; --NR.sub.7C(O)OR.sub.7;
--S(O).sub.pR.sub.7, --OS(O).sub.pR.sub.7, --OS(O).sub.pOR.sub.7,
--OS(O).sub.pNR.sub.10R.sub.11, --S(O).sub.pOR.sub.7,
--S(O).sub.pNR.sub.10R.sub.11; --NR.sub.8S(O).sub.pR.sub.7,
--NR.sub.7S(O).sub.pNR.sub.10R.sub.11,
--NR.sub.7S(O).sub.pOR.sub.7;
[0343] R.sub.46, for each occurrence, is independently, a lower
alkyl;
[0344] R.sub.400 is R.sub.p1 as described in Structural Formulas
(IA), (IA') and (IIA);
[0345] for Structural Formulas (IB), (IIIB), (VIIB), (VIIIB),
(IXB), and (XIB), R.sub.42 is --H, an optionally substituted alkyl,
an optionally substituted alkenyl, an optionally substituted
alkynyl, an optionally substituted cycloalkyl, an optionally
substituted cycloalkenyl, an optionally substituted heterocyclyl,
an optionally substituted aryl, an optionally substituted
heteroaryl, an optionally substituted aralkyl, an optionally
substituted heteraralkyl, protected hydroxyalkyl that is optionally
substituted, an optionally substituted alkoxyalkyl, an optionally
substituted haloalkyl, an optionally substituted heteroalkyl, and
--C(O)R.sub.7.
[0346] R.sub.43 and R.sub.44 are, independently, --H, --OR.sub.100,
--N(R.sub.102).sub.2, an optionally substituted alkyl, an
optionally substituted alkenyl, an optionally substituted alkynyl,
an optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted heterocyclyl, an optionally
substituted aryl, an optionally substituted heteroaryl, an
optionally substituted aralkyl, an optionally substituted
heteraralkyl, protected hydroxyalkyl, alkoxyalkyl, halo, cyano,
nitro, guanadino, a haloalkyl, a heteroalkyl, --C(O)R.sub.7, or
--SR.sub.101. Or R.sub.43 and R.sub.44 taken together with the
carbon atoms to which they are attached form an optionally
substituted cycloalkenyl, an optionally substituted aryl, an
optionally substituted heterocyclyl, or an optionally substituted
heteroaryl;
[0347] R.sub.45 is --H, --OR.sub.100, --SR.sub.101,
--N(R.sub.102).sub.2, --O(CH.sub.2).sub.mOR.sub.100,
O(CH.sub.2).sub.mSR.sub.101, --O(CH.sub.2).sub.mN(R.sub.102).sub.2,
--NR.sub.10R.sub.11, S(CH.sub.2).sub.mOR.sub.100,
--S(CH.sub.2).sub.mSR.sub.101,
--S(CH.sub.2).sub.mN(R.sub.102).sub.2, --OCH.sub.2C(O)R.sub.7,
--SCH.sub.2C(O)R.sub.7, or --NR.sub.7CH.sub.2C(O)R.sub.7; and
[0348] R.sub.46, for each occurrence, is independently, selected
from the group consisting of H, an optionally substituted alkyl, an
optionally substituted alkenyl, an optionally substituted alkynyl,
an optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted heterocyclyl, an optionally
substituted aryl, an optionally substituted heteroaryl, an
optionally substituted aralkyl, an optionally substituted
heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a
heteroalkyl, --NR.sub.10R.sub.11, --OR.sub.100, --C(O)R.sub.7, and
--SR.sub.101. Or two R.sub.46 groups taken together with the carbon
atoms to which they are attached form a fused ring;
[0349] R.sub.41 is --H, --OR.sub.A, --SR.sub.B, an optionally
substituted alkyl, an optionally substituted alkenyl, an optionally
substituted alkynyl, an optionally substituted cycloalkyl, an
optionally substituted cycloalkenyl, an optionally substituted
heterocyclyl, an optionally substituted aryl, an optionally
substituted heteroaryl, an optionally substituted aralkyl, an
optionally substituted heteraralkyl, halo, cyano, nitro, guanadino,
a haloalkyl, a heteroalkyl, an alkoxy or cycloalkoxy, a haloalkoxy,
--NR.sub.10R.sub.11 or --C(O)R.sub.7. More specifically, R.sub.4 is
selected from the group consisting of --H, a lower alkyl, a lower
alkoxy, a lower cycloalkyl and a lower cycloalkoxy.
[0350] R.sub.400 is R.sub.100 as described in Structural Formulas
(IB), (IIIB), (VIIB), (VIIIB), (IXB), and (XIB).
[0351] Values and specific values for the remainder of the
variables are as described in Structural Formulas (I)-(IV), (IA),
(IA'), (IIA), (IB), (IIIB), (VIIB), (VIIIB), (IXB) and (XIB).
[0352] In a more specific embodiment, for Structural Formulas
(I)-(IV), X.sub.41 is NR.sub.42 and X.sub.42 is CR.sub.44. The
remainder of the variables are as described in the eighteenth
specific embodiment.
[0353] In another more specific embodiment, for Structural Formulas
(I)-(IV), X.sub.41 is NR.sub.42 and X.sub.42 is N. Values and
specific values for the remainder of the variables are as described
in the eighteenth specific embodiment.
[0354] In another more specific embodiment, for Structural Formulas
(I)-(IV), R.sub.41 is selected from the group consisting of --H,
lower alkyl, lower alkoxy, lower cycloalkyl, and lower cycloalkoxy.
More specifically, R.sub.41 is selected from the group consisting
of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy,
ethoxy, propoxy, and cyclopropoxy. Values and specific values for
the remainder of the variables are as described in the eighteenth
specific embodiment.
[0355] In another more specific embodiment, for Structural Formulas
(I)-(IV), X.sub.41 is NR.sub.42, and R.sub.42 is selected from the
group consisting of --H, a lower alkyl, a lower cycloalkyl, wherein
each R.sub.27 is independently --H or a lower alkyl. More
specifically,
[0356] R.sub.42 is selected from the group consisting of --H,
methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl,
sec-butyl, tert-butyl, n-pentyl, n-hexyl, --CH.sub.2OCH.sub.3,
--CH.sub.2CH.sub.2OCH.sub.3. Values and specific values for the
remainder of the variables are as described in the eighteenth
specific embodiment.
[0357] In another more specific embodiment, for Structural Formulas
(I)-(IV), R.sub.43 and R.sub.44 are, independently, selected from
the group consisting of --H, methyl, ethyl, propyl, isopropyl,
cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy. Values and
specific values for the remainder of the variables are as described
in the eighteenth specific embodiment.
[0358] In another more specific embodiment, for Structural Formulas
(I)-(IV), X.sub.42 is CR.sub.44; Y.sub.40 is CR.sub.43; and
R.sub.43 and R.sub.44 together with the carbon atoms to which they
are attached form a cycloalkenyl, an aryl, heterocyclyl, or
heteroaryl ring. In a more specific embodiment, X.sub.41 is O. In a
even more specific embodiment, R.sub.43 and R.sub.44 together with
the carbon atoms to which they are attached form a C.sub.5-C.sub.8
cycloalkenyl or a C.sub.5-C.sub.8 aryl. In another even more
specific embodiment, R.sub.45 or CR.sub.45 is selected from the
group consisting of --H, --OR.sub.A, --SR.sub.B,
--N(R.sub.C).sub.2, a lower alkoxy, and a lower dialkyl amino. Even
more specifically, R.sub.45 is selected from the group consisting
of --H, --OR.sub.A, methoxy and ethoxy. Values and specific values
for the remainder of the variables are as described in the
eighteenth specific embodiment.
[0359] In another more specific embodiment, for Structural Formulas
(IA), (IA') and (IIA), the variables can each be independently
selected from the following lists of preferred values (values and
specific values for the remainder of the substituents are as
defined above in the eighteenth specific embodiment):
[0360] X.sub.41 can be NR.sub.42 and X.sub.42 can be CR.sub.44;
[0361] X.sub.41 can be NR.sub.42 and X.sub.42 can be N;
[0362] R.sub.41 can be selected from the group consisting of --H,
lower alkyl, lower alkoxy, lower cycloalkyl, and lower
cycloalkoxy;
[0363] R.sub.41, can be selected from the group consisting of --H,
methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy,
propoxy, and cyclopropoxy;
[0364] X.sub.41 can be NR.sub.42, and R.sub.42 can be selected from
the group consisting of --H, a lower alkyl, a lower cycloalkyl,
--C(O)N(R.sub.27).sub.2, and --R.sub.C, wherein R.sub.C is a
protected carboxyl group as defined above, and each R.sub.27 is
independently --H or a lower alkyl;
[0365] X.sub.41 can be NR.sub.42, and R.sub.42 can be selected from
the group consisting of --H, methyl, ethyl, n-propyl, isopropyl,
cyclopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl,
--R.sub.C, --(CH.sub.2).sub.mR.sub.C, --CH.sub.2OCH.sub.3,
--CH.sub.2CH.sub.2OCH.sub.3, and --C(O)N(CH.sub.3).sub.2, wherein
R.sub.C is a protected carboxyl group and m is 1 or 2;
[0366] R.sub.43 and R.sub.44 can be, independently, selected from
the group consisting of --H, methyl, ethyl, propyl, isopropyl,
cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy;
[0367] X.sub.42 can be CR.sub.44; Y.sub.40 can be CR.sub.43; and
R.sub.43 and R.sub.44 together with the carbon atoms to which they
are attached can form a cycloalkenyl, an aryl, heterocyclyl, or
heteroaryl ring;
[0368] R.sub.43 and R.sub.44 together with the carbon atoms to
which they are attached can form a C.sub.5-C.sub.8 cycloalkenyl or
a C.sub.5-C.sub.8 aryl;
[0369] R.sub.45 or CR.sub.45 can be selected from the group
consisting of --H, --OR.sub.p1, --SR.sub.p2, --NHR.sub.p3,
--N(R.sub.p3).sub.2, a lower alkoxy,
--(CH.sub.2).sub.m--NHR.sub.p3, and
--(CH.sub.2).sub.m--N(R.sub.p3).sub.2, wherein m is an integer from
1 to 6;
[0370] R.sub.45 can be selected from the group consisting of --H,
--OR.sub.p1, methoxy and ethoxy;
[0371] X.sub.41 can be O.
[0372] In another more specific embodiment, for Structural Formulas
(IB), (IIIB), (VIIB), (VIIIB), (IXB), and (XIB), R.sub.1b is --SH
or --OH; R.sub.3b and R.sub.25 are --OR.sub.100; R.sub.51 is .dbd.O
or .dbd.S. More preferably, R.sub.1b is --SH or --OH; R.sub.3b and
R.sub.25 are --OR.sub.100; R.sub.51 is .dbd.O or .dbd.S; and
R.sub.45 is selected from the group consisting of --H,
--OR.sub.100, --SR.sub.101, and --N(R.sub.102).sub.2, a lower
alkoxy and a protected lower alkyl amino. Values and specific
values for the remainder of the variables are as described above in
the eighteenth specific embodiment.
[0373] In another more specific embodiment, for Structural Formulas
(IB), (IIIB), (VIIB), (VIIIB), (IXB), and (XIB), X.sub.41 is
NR.sub.42 and X.sub.42 is CR.sub.44 or N; and values and specific
values of the remaining variables are as described above in the
eighteenth specific embodiment. More preferrably, X.sub.41 is
NR.sub.42; and R.sub.42 is selected from the group consisting of
--H, a lower alkyl, a lower cycloalkyl, and an optionally
substituted alkyl; and the values and specific values of the
remaining variables are as described above in the eighteenth
specific embodiment.
[0374] In another more specific embodiment, for Structural Formulas
(IB), (IIIB), (VIIB), (VIIIB), (IXB), and (XIB), X.sub.41 is
NR.sub.42; X.sub.42 is CR.sub.44; Y.sub.40 is CR.sub.43; and
R.sub.43 and R.sub.44, together with the carbon atoms to which they
are attached, form a cycloalkenyl, an aryl, heterocyclyl,
heteroaryl ring. The values and specific values of the remaining
variables are as described above in the eighteenth specific
embodiment.
[0375] In another more specific embodiment, for Structural Formulas
(IB), (IIIB), (VIIB), (VIIIB), (IXB), and (XIB), R.sub.1b is --OH
or --SH; and the values and specific values of the remaining
variables are as described above in the eighteenth specific
embodiment.
[0376] In a nineteenth specific embodiment, the compounds of
Structural Formulas (I)-(IV), (IA), (IA'), (IIA), (IB), (IIIB),
(VIIB), (VIIIB), (IXB) and (XIB) are defined as the following or a
tautomer, a pharmaceutically acceptable salt, solvate, clathrate,
or a prodrug thereof:
[0377] R.sub.4 is selected from the group consisting of --H,
methyl, ethyl, isopropyl, and cyclopropyl; R.sub.42 is selected
from the group consisting of --H, methyl, ethyl, n-propyl,
isopropyl, n-butyl, n-pentyl, n-hexyl,
--(CH.sub.2).sub.2OCH.sub.3;
[0378] R.sub.43 and R.sub.44 are each, independently, --H, methyl,
ethyl, or isopropyl; or R.sub.53 and R.sub.54 taken together with
the carbon atoms to which they are attached form a phenyl,
cyclohexenyl, or cyclooctenyl ring; and
[0379] R.sub.45 is selected from the group consisting of --H,
--OCH.sub.3, --OCH.sub.2CH.sub.3 and --OR.sub.400. Values and
specific values for the remainder of the variables are as described
in the nineteenth specific embodiment.
[0380] In a more specific embodiment, for Structural Formula (IIA),
R.sub.21 is O. Values and specific values for the remainder of the
variables are as described in the nineteenth specific
embodiment.
[0381] In another more specific embodiment, for Structural Formulas
(IA), (IA') and (IIA), the variables can be each be independently
selected from the following lists of preferred values:
[0382] X.sub.42 can be CR.sub.44, and R.sub.43 and R.sub.44 can be,
independently, selected from the group consisting of --H, methyl,
ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy,
and cyclopropoxy;
[0383] X.sub.42 can be CR.sub.44, and R.sub.43 and R.sub.44, taken
together with the carbon atoms to which they are attached, can form
a cycloalkenyl, aryl, heterocyclyl, or heteroaryl ring;
[0384] R.sub.43 and R.sub.44, taken together with the carbon atoms
to which they are attached, can form a C.sub.5-C.sub.8 cycloalkenyl
or a C.sub.5-C.sub.8 aryl;
[0385] X.sub.42 can be CR.sub.44; and
[0386] X.sub.42 can be N.
[0387] In another more specific embodiment, for Structural Formulas
(IB), (IIB), (IIIB), (VIIB), (VIIIB), (IXB) and (XIB), X.sub.42 is
CR.sub.44, and R.sub.43 and R.sub.44 are, independently, --H,
methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy,
propoxy, cyclopropoxy, or, taken together with the carbon atoms to
which they are attached, form a cycloalkenyl, aryl, heterocyclyl,
or heteroaryl ring. Values and specific values for the
[0388] ring A is represented by the following Structural
Formula:
##STR00093##
[0389] R.sub.5 is represented by the following Structural
Formula:
##STR00094##
wherein values and specific values for the variables are as
described in the eighteenth specific embodiment.
[0390] In a more specific embodiment, for Structural Formulas
(I)-(IV), X.sub.42 is CR.sub.44. Even more specifically, R.sub.43
and R.sub.44 are, independently, selected from the group consisting
of --H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methooxy,
ethoxy, propoxy, and cyclopropoxy. In another even more specific
embodiment, R.sub.43 and R.sub.44 taken together with the carbon
atoms to which they attached, form a cycloalkyenl, aryl,
heterocyclyl, or heteroaryl ring. Even more specifically, R.sub.43
and R.sub.44, taken together with the carbon atoms to which they
are attached, form a C.sub.5--C.sub.8 cycloalkyenyl or a
C.sub.5--C.sub.8 aryl. Values and specific values for the remainder
of the variables are as described in the nineteenth specific
embodiment.
[0391] In another more specific embodiment, for Structural Formulas
(I)-(IV), X.sub.42 is N. Values and specific values for the
remainder of the variables are as described in the nineteenth
specific embodiment.
[0392] In another more specific embodiment, for Structural Formulas
(I)-(IV), X.sub.42 is CR.sub.44 or N; remainder of the variables
are as described above in the nineteenth specific embodiment.
[0393] In another more specific embodiment, for Structural Formulas
(IB), (IIB), (IIIB), (VIIB), (VIIIB), (IXB) and (XIB), X.sub.42 is
CR.sub.44; R.sub.43 and R.sub.44 are, independently, --H, methyl,
ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy,
cyclopropoxy, or, taken together with the carbon atoms to which
they are attached, form a cycloalkenyl, aryl, heterocyclyl, or
heteroaryl ring; and R.sub.6 are selected from the group consisting
of --H, methyl, ethyl, isopropyl, and cyclopropyl. Values and
specific values for the remainder of the variables are as described
above in the nineteenth specific embodiment.
[0394] In a twentieth specific embodiment, the compounds of
Structural Formulas (I)-(IV), (IA), (IA'), (IIA), (IB), (IIIB),
(VIIB), (VIIIB), (IXB) and (XIB) are defined as the following or a
tautomer, a pharmaceutically acceptable salt, solvate, clarthrate,
or a prodrug thereof:
[0395] ring A is represented by the following Structural
Formula:
##STR00095##
[0396] R.sub.5 is represented by the following Structural
Formula:
##STR00096##
wherein:
[0397] X.sub.45 is CR.sub.54 or N;
[0398] R.sub.52 for Structural Formulas (I)-(IV), (IB), (IIIB),
(VIIB), (VIIIB), (IXB) and (XIB) is selected from the group
consisting of --H, methyl, ethyl, n-propyl, isopropyl, n-butyl,
n-pentyl, n-hexyl, --(CH.sub.2).sub.2OCH.sub.3, --CH.sub.2C(O)OH,
and --C(O)N(CH.sub.3).sub.2;
[0399] R.sub.52 for Structural Formulas (IA), (IA') and (IIA) is
selected from the group consisting of --H, methyl, ethyl, n-propyl,
isopropyl, n-butyl, n-pentyl, n-hexyl, --(CH.sub.2).sub.2OCH.sub.3,
--(CH.sub.2).sub.mR.sub.C, wherein R.sub.C is a protected carboxyl
moiety and m is 1 or 2, and --C(O)N(CH.sub.3).sub.2.
[0400] R.sub.53 and R.sub.54 are each, independently, --H, methyl,
ethyl, or isopropyl; or R.sub.53 and R.sub.54 taken together with
the carbon atoms to which they are attached form a phenyl,
cyclohexenyl, or cyclooctenyl ring;
[0401] R.sub.55 is selected from the group consisting of --H, --OH,
--OCH.sub.3, and --OCH.sub.2CH.sub.3; and
[0402] R.sub.56 is selected from the group consisting of --H,
methyl, ethyl, isopropyl, and cyclopropyl; and the remainder of the
variables are as described in the nineteenth specific
embodiment.
[0403] In a more specific embodiment, R.sub.53 is H or a lower
alkyl. Values and specific values for the remainder of the
variables are as described in the twentieth specific
embodiment.
[0404] In another more specific embodiment, X.sub.45 is CR.sub.54.
Preferably, R.sub.54 is H or a lower alkyl. Values and specific
values for the remainder of the variables are as described in the
twentieth specific embodiment.
[0405] In another specific embodiment, X.sub.45 is N. Values and
specific values for the remainder of the variables are as described
in the twentieth specific embodiment.
[0406] In a twenty-first specific embodiment, the compounds of
Structural Formulas (I)-(IV), (IA), (IA'), (IIA), (IB), (IIIB),
(VIIB), (VIIIB), (IXB) and (XIB) are defined as the following:
[0407] ring A is represented by the following Structural
Formula:
##STR00097##
[0408] R.sub.5 is represented by the following Structural
Formula:
##STR00098##
wherein:
[0409] X.sub.44, for each occurrence, is independently, O,
NR.sub.42 or C(R.sub.46).sub.2;
[0410] Y.sub.43 is NR.sub.42 or C(R.sub.46).sub.2;
[0411] Y.sub.41, Y.sub.42, Z, R.sub.41, R.sub.42, and R.sub.46 are
as described in the eighteenth specific embodiment.
[0412] In a more specific embodiment, R.sub.41 is selected from the
group consisting of --H, lower alkyl, lower alkoxy, lower
cycloalkyl, and lower cycloalkoxy. Values and specific values for
the remainder of the variables are as described in the twenty-first
specific embodiment.
[0413] In another more specific embodiment, R.sub.41 is selected
from the group consisting of --H, methyl, ethyl, propyl, isopropyl,
cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy. Values and
specific values for the remainder of the variables are as described
in the twenty-first specific embodiment.
[0414] In another more specific embodiment, R.sub.42 is selected
from the group consisting of --H, methyl, ethyl, n-propyl,
isopropyl, cyclopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl,
n-hexyl, --C(O)OH, --(CH.sub.2).sub.mC(O)OH, --CH.sub.2OCH.sub.3,
--CH.sub.2CH.sub.2OCH.sub.3, and --C(O)N(CH.sub.3).sub.2. Values
and specific values for the remainder of the variables are as
described in the twenty-first specific embodiment.
[0415] In another more specific embodiment, Y.sub.41 is CR.sub.45.
Preferably, R.sub.45 is H, a lower alkoxy, or --OH. Values and
specific values for the remainder of the variables are as described
in the twenty-first specific embodiment.
[0416] In another more specific embodiment, Y.sub.42 is CH. Values
and specific values for the remainder of the variables are as
described in the twenty-first specific embodiment.
[0417] In another more embodiment, Y.sub.43 is CH.sub.2. Values and
specific values for the remainder of the variables are as described
in the twenty-first specific embodiment.
[0418] In another more specific embodiment, Y.sub.43 is NR.sub.42,
wherein R.sub.42 is H or a lower alkyl. Values and specific values
for the remainder of the variables are as described in the
twenty-first specific embodiment.
[0419] In another more specific embodiment, one of X.sub.44 is
NR.sub.42 and the other is CH.sub.2 or C(R.sub.6).sub.2.
Preferably, one of X.sub.44 is NR.sub.42 and the other is CH.sub.2.
Values and specific values for the remainder of the variables are
as described in the twenty-first specific embodiment.
[0420] In a twenty-second specific embodiment, the compounds of
Structural Formulas (I)-(IV), (IA), (IA'), (IIA), (IB), (IIIB),
(VIIB), (VIIIB), (IXB) and (XIB) are defined as the following:
[0421] ring A is represented by the following Structural
Formula:
##STR00099##
[0422] R.sub.5 is represented by the following Structural
Formula:
##STR00100##
wherein the variables are as defined in the eighteenth specific
embodiment.
[0423] In a more specific embodiment, R.sub.41 is selected from the
group consisting of --H, lower alkyl, lower alkoxy, lower
cycloalkyl, and lower cycloalkoxy. Values and specific values for
the remainder of the variables are as described in the
twenty-second specific embodiment.
[0424] In another more specific embodiment, R.sub.41 is selected
from the group consisting of --H, methyl, ethyl, propyl, isopropyl,
cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy. The
remainder of the variables are as described in the twenty-second
specific embodiment.
[0425] In another more specific embodiment, X.sub.41 is NR.sub.42.
Preferably, R.sub.42 is selected from the group consisting of --H,
methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl,
sec-butyl, tert-butyl, n-pentyl, n-hexyl, --C(O)OH,
--(CH.sub.2).sub.mC(O)OH, --CH.sub.2OCH.sub.3,
--CH.sub.2CH.sub.2OCH.sub.3, and --C(O)N(CH.sub.3).sub.2. More
preferably, R.sub.42 is H or a lower alkyl. Values and specific
values for the remainder of the variables are as described in the
twenty-second specific embodiment.
[0426] In another more specific embodiment, X.sub.41 is O. Values
and specific values for the remainder of the variables are as
described in the twenty-second specific embodiment.
[0427] In another more specific embodiment, X.sub.41 is S. Values
and specific values for the remainder of the variables are as
described in the twenty-second specific embodiment.
[0428] In another more specific embodiment, Y.sub.41 is CR.sub.45.
Preferably, R.sub.45 is H, a lower alkoxy, or --OH. Values and
specific values for the remainder of the variables are as described
in the twenty-second specific embodiment.
[0429] In another more specific embodiment, Y.sub.42 is CH. Values
and specific values for the remainder of the variables are as
described in the twenty-second specific embodiment.
[0430] In another more specific embodiment, R.sub.46 is H or a
lower alkyl. Values and specific values for the remainder of the
variables are as described in the twenty-second specific
embodiment.
[0431] In a twenty-third specific embodiment, the compounds of
Structural Formulas (I)-(IV), (IA), (IA'), (IIA), (IB), (IIIB),
(VIIB), (VIIIB), (IXB) and (XIB) are defined as the following:
[0432] ring A is represented by the following Structural
Formula:
##STR00101##
[0433] R.sub.5 is represented by the following Structural
Formula:
##STR00102##
[0434] wherein X.sub.11, for each occurrence, is independently CH,
CR.sub.9, N, N(O), or N.sup.+(R.sub.17), provided that at least one
X.sub.11 is N, N(O), or N.sup.+(R.sub.17) and at least two X.sub.11
groups are independently selected from CH and CR.sub.9; values and
specific values for the remainder of the variables are as described
above in the tenth specific embodiment.
[0435] In a more specific embodiment, one of the X.sub.11 group is
N, N(O), or N.sup.+(R.sub.17) and the remaining X.sub.11 groups are
independently selected from CH and CR.sub.9. More specifically,
R.sub.41 is a lower alkyl, C3-C6 cycloalkyl, lower alkoxy, a lower
alkyl sulfanyl, or --NR.sub.10R.sub.11. Values and specific values
for the remainder of the variables are as described above in the
twenty-third specific embodiment.
[0436] In a twenty-fourth specific embodiment, the compound of
formula (IIA) is represented by the following Structural
Formula:
##STR00103##
wherein the variables are as described above in the eighteenth
specific embodiment.
[0437] In a more specific embodiment, the variables can each be
independently selected from the following lists of specific values
(values and specific values for the remainder of the substituents
are as defined above in the twenty-third specific embodiment):
[0438] X.sub.41 can be NR.sub.42 and X.sub.42 can be CR.sub.44;
[0439] X.sub.41 can be NR.sub.42 and X.sub.42 can be N;
[0440] R.sub.41 can be selected from the group consisting of --H,
lower alkyl, lower alkoxy, lower cycloalkyl, and lower
cycloalkoxy;
[0441] R.sub.41 can be selected from the group consisting of --H,
methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy,
propoxy, and cyclopropoxy;
[0442] X.sub.41 can be NR.sub.42, and R.sub.42 can be selected from
the group consisting of --H, a lower alkyl, a lower cycloalkyl,
--C(O)N(R.sub.27).sub.2, and --R.sub.C, wherein R.sub.C is a
protected carboxyl group as defined above, and each R.sub.27 is
independently --H or a lower alkyl;
[0443] X.sub.41 can be NR.sub.42, and R.sub.42 can be selected from
the group consisting of --H, methyl, ethyl, n-propyl, isopropyl,
cyclopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl,
--R.sub.C, --(CH.sub.2).sub.mR.sub.C, --CH.sub.2OCH.sub.3,
--CH.sub.2CH.sub.2OCH.sub.3, and --C(O)N(CH.sub.3).sub.2, wherein
R.sub.C is a protected carboxyl group and m is 1 or 2;
[0444] R.sub.43 and R.sub.44 can be, independently, selected from
the group consisting of --H, methyl, ethyl, propyl, isopropyl,
cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy;
[0445] X.sub.42 can be CR.sub.44; Y.sub.40 can be CR.sub.43; and
R.sub.43 and R.sub.44 together with the carbon atoms to which they
are attached can form a cycloalkenyl, an aryl, heterocyclyl, or
heteroaryl ring;
[0446] R.sub.43 and R.sub.44 together with the carbon atoms to
which they are attached can form a C.sub.5-C.sub.8 cycloalkenyl or
a C.sub.5-C.sub.8 aryl;
[0447] R.sub.45 or CR.sub.45 can be selected from the group
consisting of --H, --OR.sub.p1, --SR.sub.p2, --NHR.sub.p3,
--N(R.sub.p3).sub.2, a lower alkoxy,
--(CH.sub.2).sub.m--NHR.sub.p3, and
--(CH.sub.2).sub.m--N(R.sub.p3).sub.2, wherein m is an integer from
1 to 6;
[0448] R.sub.45 can be selected from the group consisting of --H,
--OR.sub.p1, methoxy and ethoxy;
[0449] X.sub.41 can be O.
[0450] In a twenty-fifth specific embodiment, the compound of
formula (IIA) is represented by the following Structural
Formula:
##STR00104##
the variables are as described above in the twenty-third specific
embodiment.
[0451] In a more specific embodiment, R.sub.21 is O. Values and
specific values for the remainder of the substituents are as
defined above in the twenty-third specific embodiment.
[0452] In another more specific embodiment, the variables can each
be independently selected from the following lists of specific
values:
[0453] X.sub.42 can be CR.sub.44, and R.sub.43 and R.sub.44 can be,
independently, selected from the group consisting of --H, methyl,
ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy,
and cyclopropoxy;
[0454] X.sub.42 can be CR.sub.44, and R.sub.43 and R.sub.44, taken
together with the carbon atoms to which they are attached, can form
a cycloalkenyl, aryl, heterocyclyl, or heteroaryl ring;
[0455] R.sub.43 and R.sub.44, taken together with the carbon atoms
to which they are attached, can form a C.sub.5-C.sub.8 cycloalkenyl
or a C.sub.5-C.sub.8 aryl;
[0456] X.sub.42 can be CR.sub.44; and
[0457] X.sub.42 can be N.
[0458] In a twenty-sixth specific embodiment, the compound of
Structural Formula (IIA) is represented by the following Structural
Formula:
##STR00105##
[0459] wherein:
[0460] X.sub.45 is CR.sub.54 or N;
[0461] R.sub.21 is O;
[0462] R.sub.56 is selected from the group consisting of --H,
methyl, ethyl, isopropyl, and cyclopropyl;
[0463] R.sub.52 is selected from the group consisting of --H,
methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl,
--(CH.sub.2).sub.2OCH.sub.3, --(CH.sub.2).sub.mR.sub.C, wherein
R.sub.C is a protected carboxyl moiety and m is 1 or 2, and
--C(O)N(CH.sub.3).sub.2;
[0464] R.sub.53 and R.sub.54 are each, independently, --H, methyl,
ethyl, or isopropyl;
[0465] or R.sub.53 and R.sub.54 taken together with the carbon
atoms to which they are attached form a phenyl, cyclohexenyl, or
cyclooctenyl ring; and
[0466] R.sub.55 is selected from the group consisting of --H, --OH,
--OCH.sub.3, and --OCH.sub.2CH.sub.3.
[0467] Values and specific values for the remainder of the
substituents are as described in the twenty-fourth specific
embodiment.
[0468] In one embodiment, the present invention is a method of
preparing a compound of Structural Formula (XXXIA)
##STR00106##
comprising the step of reacting the compound of for Structural
Formula (XXXA)
##STR00107##
with POCl.sub.3 in dimethyl formamide (DMF).
[0469] In one embodiment of the present invention, POCl.sub.3
(typically in excess over the compound of Structural Formula
(XXXA)) is added to cold DMF. Because the reaction is exothermic,
the reagents are commonly added with cooling.
[0470] The molar ration of the POCl.sub.3 to the compound of
Structural Formula (XXXA) can be, for example, 10:1, 9:1, 8:1, 7:1,
6:1, 5:1, 4:1, 3:1, 2:1, 1.5:1, 1.2:1. ort 1.1:1.
[0471] Preferably, the molar ration is 5:1 to 1.5:1. More
preferably, the moral ratio is 3:1 to 2:1.
[0472] Preferably, the product of the reaction between the compound
of Structural Formula (XXXA) and POCl.sub.3 in dimethyl formamide
(DMF) is further reacted with a hydroxide base, such as NaOH.
Typically, an excess of the base with respect to the starting
reagent is used. In one embodiment, 12 equivalents of NaOH is
used.
[0473] In Structural Formulas (XXXA) and (XXXIA), wherein R.sub.301
and R.sub.302 are each independently --H, an alkyl, an aryl, a
heteroaryl, an aralkyl, a heteraralkyl, each optionally substituted
by one or more of an alkyl, alkoxy, haloalkyl, halogen nitro, cyano
or alkyl alkanoate groups.
[0474] Preferably, R.sub.301 and R.sub.302 are each independently
--H, an optionally substituted C1-C6 alkyl, an optionally
substituted phenyl, an optionally substituted benzyl, or an
optionally substituted six-member heteroaryl. In one embodiment,
R.sub.301 and R.sub.302 are not simultaneously hydrogens.
[0475] More preferably, R.sub.301 and R.sub.302 are each
independently --H, an optionally substituted C.sub.1-C.sub.6 alkyl.
Even more preferably, R.sub.302 is H and R.sub.301 is isopropyl,
such that the compound of Structural Formula (XXXA) is compound
11A:
##STR00108##
and the compound of formula (XXXIA) is compound 12A:
##STR00109##
[0476] In another embodiment, the present invention is a method of
synthesis of a compound of formula (XXA), comprising reacting a
compound of formula (XXIA):
##STR00110##
with an oxidizing agent, thereby producing a compound of formula
(XXA):
##STR00111##
wherein Bn is a benzyl group.
[0477] The conditions for the reactions are described above with
reference to Structural Formulas (IA), (IA'), (IIA), (IIIA) and
(IVA). Preferably, the oxidizing agent is K.sub.3Fe(CN).sub.6.
[0478] Preferably, the compound of formula (XXIA) is prepared by
reacting a compound of formula (XXIIA)
##STR00112##
with a compound of formula (XXIIIA)
##STR00113##
in the presence of an acid. Preferably, a catalytic amount of acid
is used. The condition for this reaction are described above with
reference to formulas (IA), (IA'), (IIA), (IIIA) and (IVA).
[0479] Preferably, the compound of formula (XXA) is further
deprotected, thereby producing a compound of formula (XXIVA):
##STR00114##
[0480] In one embodiment, the methods of present invention further
comprises the step of deprotecting the compounds of Structural
Formulas (I), (IA) and (IB). General conditions for deprotecting
the compounds of Structural Formulas (I), (IA) and (IB) are known
in the art and depend on the nature of the protecting group used.
Examples are provided above with reference to Greene.
[0481] In another specific embodiment, the methods of the present
invention comprise the step of deprotecting the compound of the
following Structural Formula:
##STR00115##
[0482] by reaction of hydrogen in the presence of ammonium formate
in a polar solvent using Pd/C as catalyst, thereby forming a
compound represented by the following Structural Formula:
##STR00116##
More specifically, the polar solvent is ethanol. More specifically,
the reaction temperature is between 50.degree. C.-60.degree. C.
[0483] In one embodiment, for method III, the method further
comprises the step of deprotecting the compound represented by the
following Structural Formula:
##STR00117##
wherein R.sub.3b and R.sub.25 are --OR.sub.100, thereby forming a
triazole compound represented by the following Structural
Formula:
##STR00118##
[0484] The remaining values and specific values are as described
above in the fourteenth specific embodiment.
[0485] In another embodiment, for method III, the method further
comprises the step of deprotecting the thioamide compounds
represented by the following Structural Formula:
##STR00119##
[0486] wherein: [0487] R.sub.5 is represented by the following
Structural Formula:
##STR00120##
[0488] R.sub.3b and R.sub.25 are --OR.sub.100, thereby forming a
triazole compound represented by the following Structural
Formula:
##STR00121##
[0489] In another specific embodiment, the compounds represented by
Structural Formula (IVB) is deprotected, thereby forming a triazole
compound of the following Structural Formula:
##STR00122##
[0490] In a preferred embodiment, the second starting compound of
Structural Formula (LVIIIB) used in the disclosed method III is
prepared by reacting a thionation reagent with a compound
represented by the following formula:
##STR00123##
[0491] In one embodiment, the present invention comprises the step
of deprotecting a compound of Structural Formulas (I), (IA), (IB),
(IVB), (VIIB) and (XIB).
[0492] General conditions for deprotecting the compounds of
Structural Formulas (I), (IA), (IB), (IVB), (VIIB) and (XIB) are
known in the art and depend on the nature of protecting group used.
Examples are provided above with reference to Greene.
[0493] In one embodiment, where a benzyl group is employed as a
protecting group, the deprotection of compounds of Structural
Formulas (I), (IA), (IB), (IVB), (VIIB) and (XIB) can be
accomplished by catalytic hydrogenation. Any hydrogenation catalyst
can be used, either soluble or insoluble in the reaction medium.
Typical catalysts include palladium-on-charcoal, Raney nickel,
NaBH.sub.4-reduced nickel, platinum metal or its oxide, rhodium
ruthenium or zinc oxide. Hydrogenation reactions are typically
carried out at temperature from about 0.degree. C. to about
50.degree. C., preferably at 15-35.degree. C. at atmospheric or
slightly above atmospheric pressure.
[0494] The compounds of Structural Formulas (I), (IA), (IB), (IVB),
(VIIB) and (XIB) are typically reacted with hydrogen at room
temperature in a polar solvent. Preferably, palladium-on-charcoal
is used as a catalyst.
[0495] The polar solvent can be one or more of a polar protic
solvent, such as water or an alcohol; an ethereal solvent such as
THF, dioxane and the like. For example, the solvent can be a
mixture of THF and methanol. The mixture (by volume) can be 10:1,
9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5,
1:6, 1:7, 1:8, 1:8, 1:9, or 1:10. Preferably, the THF/MeOH mixture
is from about 4:1 to about 1:1 by volume.
[0496] In a specific embodiment, when R.sub.3 of Structural Formula
(I) is --OR.sub.A; R.sub.20 in Structural Formula (IA) is
--OR.sub.p1; or R.sub.3b of Structural Formula (IB) is
--OR.sub.100, wherein R.sub.A, R.sub.p1 and R.sub.100 are benzyl
groups, the deprotection step of compounds of Structural Formulas
(I), (IA), (IB), (IVB), (VIIB) and (XIB) comprises reacting a
compound of Structural Formulas (I), (IA), (IB), (IVB), (VIIB) and
(XIB) with ammonium formate in the presence of a hydrogen catalyst.
In one aspect, the hydrogen catalyst is palladium on activated
carbon. In one aspect, the step of deprotecting is carried out at a
temperature from 45 to 65.degree. C. In one aspect, the step of
deprotecting is carried out at about 55.degree. C. In one aspect,
the compound of Structural Formulas (I), (IA), (IB), (IVB), (VIIB)
or (XIB) and the ammonium formate are reacted for about 1 to 5
hours in the presence of the palladium on activated carbon. In one
aspect, the compound of Structural Formulas (I), (IA) or (IB) and
the ammonium formate are reacted for about 1 hour in the presence
of the palladium on activated carbon. In one aspect, the compound
of Structural Formulas (I), (IA) or (IB) and the ammonium formate
are reacted for about 12 hours in the presence of the palladium on
activated carbon. In one aspect, the purity of the deprotected
product of a compound of Structural Formulas (I), (IA), (IB),
(IVB), (VIIB) or (XIB) is 99.0% or greater. In another aspect, the
purity is 99.5% or greater. In a further aspect, the purity is
99.8% or greater.
[0497] Specific examples of compounds which can be prepared by the
disclosed method III are provided below: [0498]
3-(2-Hydroxyphenyl)-4-(naphthalen-1-yl)-5-mercapto-triazole; [0499]
3-(2,4-Dihydroxyphenyl)-4-[4-(2-methoxyethoxy)-naphthalen-1-yl]-5-mercapt-
o-triazole; [0500]
3-(2,4-Dihydroxyphenyl)-4-(2-methyl-4-bromophenyl)-5-mercapto-triazole;
[0501]
3-(3,4-Dihydroxyphenyl)-4-(6-methoxy-naphthalen-1-yl)-5-mercapto-t-
riazole; [0502]
3-(3,4-Dihydroxyphenyl)-4-(6-ethoxy-naphthalen-1-yl)-5-mercapto-triazole;
[0503]
3-(3,4-Dihydroxyphenyl)-4-(6-propoxy-naphthalen-1-yl)-5-mercapto-t-
riazole; [0504]
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(5-methoxy-naphthalen-1-yl)-5-mercapto-
-triazole; [0505]
3-(3,4-Dihydroxyphenyl)-4-(6-isopropoxy-naphthalen-1-yl)-5-mercapto-triaz-
ole; [0506]
3-(2,4-Dihydroxyphenyl)-4-(2,6-diethylphenyl)-5-mercapto-triazole;
[0507]
3-(2,4-Dihydroxyphenyl)-4-(2-methyl-6-ethylphenyl)-5-mercapto-triazole;
[0508]
3-(2,4-Dihydroxyphenyl)-4-(2,6-diisopropylphenyl)-5-mercapto-triaz-
ole; [0509]
3-(2,4-Dihydroxyphenyl)-4-(1-ethyl-indol-4-yl)-5-mercapto-triazole;
[0510]
3-(2,4-Dihydroxyphenyl)-4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-5-me-
rcapto-triazole; [0511]
3-(2,4-Dihydroxyphenyl)-4-(3-methylphenyl)-5-mercapto-triazole;
[0512]
3-(2,4-Dihydroxyphenyl)-4-(4-methylphenyl)-5-mercapto-triazole;
[0513]
3-(2,4-Dihydroxyphenyl)-4-(2-chlorophenyl)-5-mercapto-triazole;
[0514]
3-(2,4-Dihydroxyphenyl)-4-(3-chlorophenyl)-5-mercapto-triazole;
[0515]
3-(2,4-Dihydroxyphenyl)-4-(4-chlorophenyl)-5-mercapto-triazole;
[0516]
3-(2,4-Dihydroxyphenyl)-4-(2-methoxyphenyl)-5-mercapto-triazole;
[0517]
3-(2,4-Dihydroxyphenyl)-4-(3-methoxyphenyl)-5-mercapto-triazole;
[0518]
3-(2,4-Dihydroxyphenyl)-4-(3-fluorophenyl)-5-mercapto-triazole;
[0519]
3-(2,4-Dihydroxyphenyl)-4-(2-ethylphenyl)-5-mercapto-triazole;
[0520]
3-(2-Hydroxy-4-fluorophenyl)-4-(naphthalen-1-yl)-5-mercapto-triazole;
[0521]
3-(2-Hydroxy-4-aminophenyl)-4-(naphthalen-1-yl)-5-mercapto-triazol-
e; [0522]
3-(2,4-Dihydroxyphenyl)-4-(2-methyl-4-butyl-phenyl)-5-mercapto-t-
riazole; [0523]
3-(2,4-Dihydroxyphenyl)-4-(2,4-dimethyl-phenyl)-5-mercapto-triazole;
[0524]
3-(2,4-Dihydroxyphenyl)-4-(2,6-dimethyl-phenyl)-5-mercapto-triazol-
e; [0525]
3-(2,4-Dihydroxyphenyl)-4-(2,6-dimethyl-phenyl)-5-mercapto-triaz-
ole; [0526]
3-(2,4-Dihydroxyphenyl)-4-(4-fluorophenyl)-5-mercapto-triazole;
[0527]
3-(2,4-Dihydroxyphenyl)-4-(2-methylsulfanylphenyl)-5-mercapto-triazole;
[0528]
3-(2,4-Dihydroxyphenyl)-4-(naphthalene-2-yl)-5-mercapto-triazole;
[0529]
3-(2,4-Dihydroxyphenyl)-4-(2,3-dimethylphenyl)-5-mercapto-triazole-
; [0530]
3-(2,4-Dihydroxyphenyl)-4-(2-methyl-4-fluorophenyl)-5-mercapto-tr-
iazole; [0531]
3-(2,4-Dihydroxyphenyl)-4-(acenaphthalen-5-yl)-5-mercapto-triazole;
[0532]
3-(2-Hydroxy-4-methoxy-phenyl)-4-(naphthalen-1-yl)-5-mercapto-tria-
zole; [0533]
3-(2,4-Dihydroxyphenyl)-4-(2,3-dichlorophenyl)-5-mercapto-triazole;
[0534]
3-(2,4-Dihydroxyphenyl)-4-(5-methoxynaphthalen-1-yl)-5-mercapto-tr-
iazole; [0535]
3-(2,4-Dihydroxyphenyl)-4-(pyren-1-yl)-5-mercapto-triazole; [0536]
3-(2,4-Dihydroxyphenyl)-4-(quinolin-5-yl)-5-mercapto-triazole;
[0537]
3-(2,4-Dihydroxyphenyl)-4-(1,2,3,4-tetrahydronaphthalen-5-yl)-5-me-
rcapto-triazole; [0538]
3-(2,4-Dihydroxyphenyl)-4-(anthracen-1-yl)-5-mercapto-triazole;
[0539]
3-(2,4-Dihydroxyphenyl)-4-(biphenyl-2-yl)-5-mercapto-triazole;
[0540]
3-(2,4-Dihydroxy-6-methyl-phenyl)-4-(naphthalene-1-yl)-5-mercapto-triazol-
e; [0541]
3-(2,4-Dihydroxyphenyl)-4-(4-pentyloxyphenyl)-5-mercapto-triazol-
e; [0542]
3-(2,4-Dihydroxyphenyl)-4-(4-octyloxyphenyl)-5-mercapto-triazole- ;
[0543]
3-(2,4-Dihydroxyphenyl)-4-(4-chloronaphthalen-1-yl)-5-mercapto-tr-
iazole; [0544]
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(naphthalen-1-yl)-5-mercapto-triazole;
[0545]
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(7-carboxymethoxy-naphthalen-1--
yl)-5-mercapto-triazole; [0546]
3-(2,4-Dihydroxyphenyl)-4-(2-methyl-quinolin-4-yl)-5-mercapto-triazole;
[0547]
3-(3-Hydroxypyridin-4-yl)-4-(naphthalen-1-yl)-5-mercapto-triazole;
[0548]
3-(2-Hydroxy-4-acetylamino-phenyl)-4-(naphthalen-1-yl)-5-mercapto--
triazole; [0549]
3-(2,4-Dihydroxy-phenyl)-4-(1,2,3,4-tetrahydronaphthalen-1-yl)-5-mercapto-
-triazole; [0550]
3-(2,4-Dihydroxy-phenyl)-4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-5-mercapto-
-triazole; [0551]
3-(2,4-Dihydroxy-phenyl)-4-(3,5-dimethoxyphenyl)-5-mercapto-triazole;
[0552]
3-(2,4-Dihydroxy-phenyl)-4-(2,3-dimethyl-1H-indol-4-yl)-5-mercapto-
-triazole; [0553]
3-(2,4-Dihydroxy-3-propyl-phenyl)-4-(naphthalen-1-yl)-5-mercapto-triazole-
; [0554]
3-(4,6-Dihydroxy-1-ethyl-pyridin-3-yl)-4-(naphthalen-1-yl)-5-merc-
apto-triazole; [0555]
3-(4,6-Dihydroxy-1-methyl-pyridin-3-yl)-4-(naphthalen-1-yl)-5-mercapto-tr-
iazole; [0556]
3-(2,4-Dihydroxy-phenyl)-4-(3,5-di-tert-butylphenyl)-5-mercapto-triazole;
[0557]
3-(2,6-Dihydroxy-5-fluoro-pyridin-3-yl)-4-(naphthalen-1-yl)-5-merc-
apto-triazole; [0558]
3-(2,4-Dihydroxy-5-methyl-phenyl)-4-(naphthalene-1-yl)-5-mercapto-triazol-
e; [0559]
3-[2,4-Dihydroxy-phenyl]-4-(3-benzoylphenyl)-5-mercapto-triazole- ;
[0560]
3-(2,4-Dihydroxy-phenyl)-4-(4-carboxy-naphthalen-1-yl)-5-mercapto-
-triazole; [0561]
3-(2,4-Dihydroxy-phenyl)-4-[4-(N,N-dimethylcarbamoyl)-naphthalen-1-yl]-5--
mercapto-triazole; [0562]
3-(2,4-Dihydroxy-phenyl)-4-(4-propoxy-naphthalen-1-yl)-5-mercapto-triazol-
e; [0563]
3-(2,4-Dihydroxy-phenyl)-4-(4-isopropoxy-naphthalen-1-yl)-5-merc-
apto-triazole; [0564]
3-(2,4-Dihydroxy-phenyl)-4-(5-isopropoxy-naphthalen-1-yl)-5-mercapto-tria-
zole; [0565]
3-(2,4-Dihydroxy-phenyl)-4-(isoquinolin-5-yl)-5-mercapto-triazole;
[0566]
3-(2,4-Dihydroxy-phenyl)-4-(5-propoxy-naphthalen-1-yl)-5-mercapto-triazol-
e; [0567]
3-(2-Hydroxy-4-methanesulfonamino-phenyl)-4-(naphthalen-1-yl)-5--
mercapto-triazole; [0568]
3-(2,4-Dihydroxy-3,6-dimethyl-phenyl)-4-(naphthalen-1-yl)-5-mercapto-tria-
zole; [0569]
3-(2,4-Dihydroxy-phenyl)-4-[7-(2-methoxyethoxy)-naphthalen-1-yl]-5-mercap-
to-triazole; [0570]
3-(2,4-Dihydroxy-5-hexyl-phenyl)-4-(naphthalen-1-yl)-5-mercapto-triazole;
[0571]
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(4-methoxy-naphthalen-1-yl)-5-m-
ercapto-triazole; [0572]
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(6-methoxy-naphthalin-1-yl)-5-mercapto-
-triazole; [0573]
3-(2,4-Dihydroxy-3-chloro-5-ethyl-phenyl)-4-(naphthalen-1-yl)-5-mercapto--
triazole; [0574]
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(2,3-dimethyl-4-methoxy-phenyl)-5-merc-
apto-triazole; [0575]
3-(2,4-Dihydroxy-phenyl)-4-(7-isopropoxy-naphthalen-1-yl)-5-mercapto-tria-
zole; [0576]
3-(2,4-Dihydroxy-phenyl)-4-(7-ethoxy-naphthalen-1-yl)-5-mercapto-triazole-
; [0577]
3-(2,4-Dihydroxy-phenyl)-4-(7-propoxy-naphthalen-1-yl)-5-mercapto-
-triazole; [0578]
3-(2-Hydroxy-4-methoxymethyoxy-phenyl)-4-(naphthalen-1-yl)-5-mercapto-tri-
azole; [0579]
3-[2-Hydroxy-4-(2-hydroxy-ethoxy)-phenyl]-4-(naphthalen-1-yl)-5-mercapto--
triazole; [0580]
3-(2,4-Dihydroxyphenyl)-4-(7-methoxy-naphthalen-1-yl)-5-mercapto-triazole-
; [0581]
3-(2,4-Dihydroxyphenyl)-4-(5-methoxy-naphthalen-1-yl)-5-mercapto--
triazole; [0582]
3-(2,4-Dihydroxyphenyl)-4-(4-hydroxy-naphthalen-1-yl)-5-mercapto-triazole-
; [0583]
3-(2,4-Dihydroxyphenyl)-4-(1-isopropyl-indol-4-yl)-5-mercapto-tri-
azole; [0584]
3-(2,4-Dihydroxy-5-tert-butyl-phenyl)-4-(naphthalen-1-yl)-5-mercapto-tria-
zole; [0585]
3-(2,4-Dihydroxy-5-propyl-phenyl)-4-(naphthalen-1-yl)-5-mercapto-triazole-
; [0586]
3-(2,4-Dihydroxy-3-methyl-5-ethyl-phenyl)-4-(naphthalen-1-yl)-5-m-
ercapto-triazole; [0587]
3-(2,4-Dihydroxy-5-isobutyl-phenyl)-4-(naphthalen-1-yl)-5-mercapto-triazo-
le; [0588]
3-(2,4-Dihydroxy-phenyl)-4-(2,3-dimethoxy-phenyl)-5-mercapto-tr-
iazole; [0589]
3-(2,4-Dihydroxy-phenyl)-4-(2-methoxy-3-chloro-phenyl)-5-mercapto-triazol-
e; [0590]
3-(2,4-Dihydroxy-phenyl)-4-(indol-4-yl)-5-mercapto-triazole; [0591]
3-(2,4-Dihydroxy-phenyl)-4-[1-(2-methoxyethoxy)-indol-4-yl]-5-merc-
apto-triazole; [0592]
3-(2,4-Dihydroxy-phenyl)-4-(naphthalen-1-yl)-5-hydroxy-triazole;
[0593]
3-(1-Oxo-3-hydroxy-pyridin-4-yl)-4-(naphthalen-1-yl)-5-mercapto-triazole;
[0594]
3-(2,5-Dihydroxy-4-carboxy)-4-(naphthalen-1-yl)-5-mercapto-triazol-
e; [0595]
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(1-isopropyl-indol-4-yl)-5-me-
rcapto-triazole; [0596]
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-[1-(dimethyl-carbamoyl)-indol-4-yl]-5--
mercapto-triazole; [0597]
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(1-ethyl-benzoimidazol-4-yl)-5-mercapt-
o-triazole; [0598]
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(1,2,3-trimethyl-indol-5-yl)-5-mercapt-
o-triazole; [0599]
3-(2,5-Dihydroxy-4-hydroxymethyl-phenyl)-4-(naphthalen-1-yl)-5-mercapto-t-
riazole; [0600]
3-(2-Hydroxy-4-amino-phenyl)-4-(naphthalen-1-yl)-5-mercapto-triazole;
[0601]
3-(2-Hydroxy-4-acetylamino-phenyl)-4-(naphthalen-1-yl)-5-mercapto--
triazole; [0602]
3-(2,4-Dihydroxy-3-chloro-phenyl)-4-(naphthalen-1-yl)-5-mercapto-triazole-
; [0603]
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(3-methox-phenyl)-5-hydroxy-tr-
iazole; [0604]
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(naphthalen-1-yl)-5-hydroxy-triazole;
[0605]
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(1-isopropyl-indol-3-yl)-5-hydr-
oxy-triazole; [0606]
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(1-isopropyl-indol-4-yl)-5-amino-triaz-
ole; [0607]
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(3-methoxy-phenyl)-5-amino-triazole;
[0608]
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(naphthalen-1-yl)-5-amino-triaz-
ole; [0609]
3-(2-Hydroxy-5-ethyloxy-phenyl)-4-(naphthalen-1-yl)-5-hydroxy-triazole;
[0610]
3-(2-Hydroxy-5-isopropyl-phenyl)-4-(naphthalen-1-yl)-5-hydroxy-tri-
azole; [0611]
3-(2-Dihydroxy-phenyl)-4-(7-fluoro-naphthalen-1-yl)-5-hydroxy-triazole;
[0612]
3-(2,4-Dihydroxy-phenyl)-4-(2,3-difluorophenyl)-5-hydroxy-triazole-
; [0613]
3-(2,4-Dihydroxy-phenyl)-4-[2-(1H-tetrazol-5-yl)-phenyl]-5-hydrox-
y-triazole; [0614]
3-(2,4-Dihydroxy-phenyl)-4-(benzothiazol-4-yl)-5-hydroxy-triazole;
[0615]
3-(2,4-Dihydroxy-phenyl)-4-(9H-purin-6-yl)-5-hydroxy-triazole;
[0616]
3-(2,4-Dihydroxy-phenyl)-4-{4-[2-(moropholin-1-yl)-ethoxy]-phenyl}-5-hydr-
oxy-triazole; [0617]
3-(2,4-Dihydroxy-phenyl)-4-cyclopentyl-5-hydroxy-triazole; [0618]
3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(naphthalen-1-yl)-5-mercapto-triazol-
e; [0619]
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(5-hydroxy-naphthalen-1-yl)-5-
-mercapto-triazole; [0620]
3-(2,4-Dihydroxy-phenyl)-4-(naphthalen-1-ylmethyl)-5-mercapto-triazole;
[0621]
3-(2-Hydroxy-4-methoxyphenyl)-4-(naphthalen-1-yl)-5-mercapto-triaz-
ole; [0622]
3-(2,4-Dihydroxy-phenyl)-4-(biphenyl-3-yl)-5-mercapto-triazole;
[0623]
3-(2,4-Dihydroxy-phenyl)-4-(2-methyl-5-hydroxymethyl-phenyl)-5-mercapto-t-
riazole; [0624]
3-(2,4-Dihydroxy-phenyl)-4-(1-dimethylcarbamoyl-indol-4-yl)-5-mercapto-tr-
iazole; [0625]
3-(2,4,5-Trihydroxy-phenyl)-4-(naphthalene-1-yl)-5-mercapto-triazole;
[0626]
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(2,3-dimethyl-indol-5-yl)-5-mer-
capto-triazole; [0627]
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(3-t-butyl-4-methoxy-phenyl)-5-mercapt-
o-triazole; [0628]
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(1-ethyl-1H-benzoimidazol-4-yl)-5-merc-
apto-triazole, HCl salt; [0629]
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(1-isopropyl-7-methoxy-indol-4-yl)-5-m-
ercapto-triazole; and [0630]
3-(2,4-Dihydroxy-5-cyclopropyl-phenyl)-4-(naphthalene-1-yl)-5-mercapto-tr-
iazole, or a tautomer, pharmaceutically acceptable salt, solvate,
clathrate or prodrug thereof.
[0631] Exemplary compounds that can be prepared by the disclosed
method I and method III are depicted in Tables 1 and 2 below,
including tautomers, pharmaceutically acceptable salts, solvates,
clathrates, hydrates, polymorphs or prodrugs and synthetic
intermediates thereof represented by Structural Formula (II),
(III), or (IV). Exemplary compounds that can be prepared by the
disclosed method II include compounds 97, 137-173, 176, 220, and
232 depicted in Table 1 below.
TABLE-US-00001 TABLE 1 No. Structure Tautomeric Structure Name 1
##STR00124## ##STR00125##
3-(2-Hydroxyphenyl)-4-(naphthalen-1-yl)-5-mercapto-[1,2,4]triazole
2 ##STR00126## ##STR00127##
3-(2,4-Dihydroxyphenyl)-4-[4-(2-methoxyethoxy)-naphthalen-1-yl]-5-mercapt-
o-[1,2,4]triazole 3 ##STR00128## ##STR00129##
3-(2,4-Dihydroxyphenyl)-4-(2-methyl-4-bromophenyl)-5-mercapto-[1,2,4]tria-
zole 4 ##STR00130## ##STR00131##
3-(2,4-Dihydroxyphenyl)-4-(4-bromophenyl)-5-mercapto-[1,2,4]triazole
5 ##STR00132## ##STR00133##
3-(3,4-Dihydroxyphenyl)-4-(6-methoxy-naphthalen-1-yl)-5-mercapto-[1,2,4]t-
riazole 6 ##STR00134## ##STR00135##
3-(3,4-Dihydroxyphenyl)-4-(6-ethoxy-naphthalen-1-yl)-5-mercapto-[1,2,4]tr-
iazole 7 ##STR00136## ##STR00137##
3-(3,4-Dihydroxyphenyl)-4-(6-propoxy-naphthalen-1-yl)-5-mercapto-[1,2,4]t-
riazole 8 ##STR00138## ##STR00139##
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(5-methoxy-naphthalen-1-yl)-5-mercapto-
-[1,2,4]triazole 9 ##STR00140## ##STR00141##
3-(3,4-Dihydroxyphenyl)-4-(6-isopropoxy-naphthalen-1-yl)-5-mercapto-[1,2,-
4]triazole 10 ##STR00142## ##STR00143##
3-(2,4-Dihydroxyphenyl)-4-(2,6-diethylphenyl)-5-mercapto-[1,2,4]triazole
11 ##STR00144## ##STR00145##
3-(2,4-Dihydroxyphenyl)-4-(2-methy-6-ethylphenyl)-5-mercapto-[1,2,4]triaz-
ole 12 ##STR00146## ##STR00147##
3-(2,4-Dihydroxyphenyl)-4-(2,6-diisopropylphenyl)-5-mercapto-[1,2,4]triaz-
ole 13 ##STR00148## ##STR00149##
3-(2,4-Dihydroxyphenyl)-4-(1-ethyl-indol-4-yl)-5-mercapto-[1,2,4]triazole
14 ##STR00150## ##STR00151##
3-(2,4-Dihydroxyphenyl)-4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-5-mercapto--
[1,2,4]triazole 15 ##STR00152## ##STR00153##
3-(2,4-Dihydroxyphenyl)-4-(3-methylphenyl)-5-mercapto-[1,2,4]triazole
16 ##STR00154## ##STR00155##
3-(2,4-Dihydroxyphenyl)-4-(4-methylphenyl)-5-mercapto-[1,2,4]triazole
17 ##STR00156## ##STR00157##
3-(2,4-Dihydroxyphenyl)-4-(2-chlorophenyl)-5-mercapto-[1,2,4]triazole
18 ##STR00158## ##STR00159##
3-(2,4-Dihydroxyphenyl)-4-(3-chlorophenyl)-5-mercapto-[1,2,4]triazole
19 ##STR00160## ##STR00161##
3-(2,4-Dihydroxyphenyl)-4-(4-chlorophenyl)-5-mercapto-[1,2,4]triazole
20 ##STR00162## ##STR00163##
3-(2,4-Dihydroxyphenyl)-4-(2-methoxyphenyl)-5-mercapto-[1,2,4]triazole
21 ##STR00164## ##STR00165##
3-(2,4-Dihydroxyphenyl)-4-(3-methoxyphenyl)-5-mercapto-[1,2,4]triazole
22 ##STR00166## ##STR00167##
3-(2,4-Dihydroxyphenyl)-4-(4-methoxyphenyl)-5-mercapto-[1,2,4]triazole
23 ##STR00168## ##STR00169##
3-(2,4-Dihydroxyphenyl)-4-(3-fluorophenyl)-5-mercapto-[1,2,4]triazole
24 ##STR00170## ##STR00171##
3-(2,4-Dihydroxyphenyl)-4-(2-ethylphenyl)-5-mercapto-[1,2,4]triazole
25 ##STR00172## ##STR00173##
3-(2-Hydroxy-4-fluorophenyl)-4-(naphthalen-1-yl)-5-mercapto-[1,2,4]triazo-
le 26 ##STR00174## ##STR00175##
3-(2-Hydroxy-4-aminophenyl)-4-(naphthalen-1-yl)-5-mercapto-[1,2,4]triazol-
e 27 ##STR00176## ##STR00177##
3-(2,4-Dihydroxyphenyl)-4-(2-methyl-4-butyl-phenyl)-5-mercapto-[1,2,4]tri-
azole 28 ##STR00178## ##STR00179##
3-(2,4-Dihydroxyphenyl)-4-(2,4-dimethyl-phenyl)-5-mercapto-[1,2,4]triazol-
e 29 ##STR00180## ##STR00181##
3-(2,4-Dihydroxyphenyl)-4-(2,6-dimethyl-phenyl)-5-mercapto-[1,2,4]triazol-
e 30 ##STR00182## ##STR00183##
3-(2,4-Dihydroxyphenyl)-4-(2,6-dimethyl-phenyl)-5-mercapto-[1,2,4]triazol-
e 31 ##STR00184## ##STR00185##
3-(2,4-Dihydroxyphenyl)-4-(4-fluorophenyl)-5-mercapto-[1,2,4]triazole
32 ##STR00186## ##STR00187##
3-(2,4-Dihydroxyphenyl)-4-(2-methylsulfanylphenyl)-5-mercapto-[1,2,4]tria-
zole 33 ##STR00188## ##STR00189##
3-(2,4-Dihydroxyphenyl)-4-(naphthalene-2-yl)-5-mercapto-[1,2,4]triazole
34 ##STR00190## ##STR00191##
3-(2,4-Dihydroxyphenyl)-4-(2,3-dimethylphenyl)-5-mercapto-[1,2,4]triazole
35 ##STR00192## ##STR00193##
3-(2,4-Dihydroxyphenyl)-4-(2-methyl-4-fluorophenyl)-5-mercapto-[1,2,4]tri-
azole 36 ##STR00194## ##STR00195##
3-(2,4-Dihydroxyphenyl)-4-(acenaphthalen-5-yl)-5-mercapto-[1,2,4]triazole
37 ##STR00196## ##STR00197##
3-(2-Hydroxy-4-methoxy-phenyl)-4-(naphthalen-1-yl)-5-mercapto-[1,2,4]tria-
zole 38 ##STR00198## ##STR00199##
3-(2,4-Dihydroxyphenyl)-4-(2,3-dichlorophenyl)-5-mercapto-[1,2,4]triazole
39 ##STR00200## ##STR00201##
3-(2,4-Dihydroxyphenyl)-4-(5-methoxynaphthalen-1-yl)-5-mercapto-[1,2,4]tr-
iazole 40 ##STR00202## ##STR00203##
3-(2,4-Dihydroxyphenyl)-4-(pyren-1-yl)-5-mercapto-[1,2,4]triazole
41 ##STR00204## ##STR00205##
3-(2,4-Dihydroxyphenyl)-4-(quinolin-5-yl)-5-mercapto-[1,2,4]triazole
42 ##STR00206## ##STR00207##
3-(2,4-Dihydroxyphenyl)-4-(1,2,3,4-tetrahydronaphthalen-5-yl)-5-mercapto--
[1,2,4]triazole 43 ##STR00208## ##STR00209##
3-(2,4-Dihydroxyphenyl)-4-(anthracen-1-yl)-5-mercapto-[1,2,4]triazole
44 ##STR00210## ##STR00211##
3-(2,4-Dihydroxyphenyl)-4-(biphenyl-2-yl)-5-mercapto-[1,2,4]triazole
45 ##STR00212## ##STR00213##
3-(2,4-Dihydroxy-6-methyl-phenyl)-4-(naphthalene-1-yl)-5-mercapto-[1,2,4]-
triazole 46 ##STR00214## ##STR00215##
3-(2,4-Dihydroxyphenyl)-4-(4-pentyloxyphenyl)-5-mercapto-[1,2,4]triazole
47 ##STR00216## ##STR00217##
3-(2,4-Dihydroxyphenyl)-4-(4-octyloxyphenyl)-5-mercapto-[1,2,4]triazole
48 ##STR00218## ##STR00219##
3-(2,4-Dihydroxyphenyl)-4-(4-chloronaphthalen-1-yl)-5-mercapto-[1,2,4]tri-
azole 49 ##STR00220## ##STR00221##
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(naphthalen-1-yl)-5-mercapto-[1,2,4]tr-
iazole 50 ##STR00222## ##STR00223##
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(7-carboxymethoxy-naphthalen-1-yl)-5-m-
ercapto-[1,2,4]triazole 51 ##STR00224## ##STR00225##
3-(2,4-Dihydroxyphenyl)-4-(2-methyl-quinolin-4-yl)-5-mercapto-[1,2,4]tria-
zole 52 ##STR00226## ##STR00227##
3-(3-Hydroxypyridin-4-yl)-4-(naphthalen-1-yl)-5-mercapto-[1,2,4]triazole
53 ##STR00228## ##STR00229##
3-(2-Hydroxy-4-acetylamino-phenyl)-4-(naphthalen-1-yl)-5-mercapto-[1,2,4]-
triazole 54 ##STR00230## ##STR00231##
3-(2,4-Dihydroxy-phenyl)-4-(1,2,3,4-tetrahydronaphthalen-1-yl)-5-mercapto-
-[1,2,4]triazole 55 ##STR00232## ##STR00233##
3-(2,4-Dihydroxy-phenyl)-4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-5-mercapto-
-[1,2,4]triazole 56 ##STR00234## ##STR00235##
3-(2,4-Dihydroxy-phenyl)-4-(3,5-dimethoxyphenyl)-5-mercapto-[1,2,4]triazo-
le 57 ##STR00236## ##STR00237##
3-(2,4-Dihydroxy-phenyl)-4-(2,3-dimethyl-1H-indol-4-yl)-5-mercapto-[1,2,4-
]triazole 58 ##STR00238## ##STR00239##
3-(2,4-Dihydroxy-3-propyl-phenyl)-4-(naphthalen-1-yl)-5-mercapto-[1,2,4]t-
riazole 59 ##STR00240## ##STR00241##
3-(1-ethyl-4-hydroxy-6-oxo-1,6-dihydro-pyridin-3-yl)-4-(naphthalen-1-yl)--
5-mercapto-[1,2,4]triazole 60 ##STR00242## ##STR00243##
3-(4-hydroxy-6-oxo-pyridin-3-yl)-4-(naphthalen-1-yl)-5-mercapto-[1,2,4]tr-
iazole 61 ##STR00244## ##STR00245##
3-(2,4-Dihydroxy-phenyl)-4-(3,5-di-tert-butylphenyl)-5-mercapto-[1,2,4]tr-
iazole 62 ##STR00246## ##STR00247##
3-(2,6-Dihydroxy5-fluoro-pyridin-3-yl)
4-(naphthalen-1-yl)-5-mercapto-[1,2,4]triazole 63 ##STR00248##
##STR00249##
3-(2,4-Dihydroxy-5-methyl-phenyl)-4-(naphthalene-1-yl)-5-mercapto-[1,2,4]-
triazole 64 ##STR00250## ##STR00251##
3-[2,4-Dihydroxy-phenyl]-4-(3-benzoylphenyl)-5-mercapto-[1,2,4]triazole
65 ##STR00252## ##STR00253##
3-(2,4-Dihydroxy-phenyl)-4-(4-carboxy-naphthalen-1-yl)-5-mercapto-[1,2,4]-
triazole 66 ##STR00254## ##STR00255##
3-(2,4-Dihydroxy-phenyl)-4-[4-(N,N-dimethylcarbamoyl)-naphthalen-1-yl]-5--
mercapto-[1,2,4]triazole 67 ##STR00256## ##STR00257##
3-(2,4-Dihydroxy-phenyl)-4-(4-propoxy-naphthalen-1-yl)-5-mercapto-[1,2,4]-
triazole 68 ##STR00258## ##STR00259##
3-(2,4-Dihydroxy-phenyl)-4-(4-isopropoxy-naphthalen-1-yl)-5-mercapto-[1,2-
,4]triazole 69 ##STR00260## ##STR00261##
3-(2,4-Dihydroxy-phenyl)-4-(5-isopropoxy-naphthalen-1-yl)-5-mercapto-[1,2-
,4]triazole 70 ##STR00262## ##STR00263##
3-(2,4-Dihydroxy-phenyl)-4-(isoquinolin-5-yl)-5-mercapto-[1,2,4]triazole
71 ##STR00264## ##STR00265##
3-(2,4-Dihydroxy-phenyl)-4-(5-propoxy-naphthalen-1-yl)-5-mercapto-[1,2,4]-
triazole 72 ##STR00266## ##STR00267##
3-(2-Hydroxy-4-methanesulfonamino-phenyl)-4-(naphthalen-1-yl)-5-mercapto--
[1,2,4]triazole 73 ##STR00268## ##STR00269##
3-(2,4-Dihydroxy-3,6-dimethyl-phenyl)-4-(naphthalen-1-yl)-5-mercapto-[1,2-
,4]triazole 74 ##STR00270## ##STR00271##
3-(2,4-Dihydroxy-phenyl)-4-[7-(2-methoxyethoxy)-naphthalen-1-yl]-5-mercap-
to-[1,2,4]triazole 75 ##STR00272## ##STR00273##
3-(2,4-Dihydroxy-5-hexyl-phenyl)-4-(naphthalen-1-yl)-5-mercapto-[1,2,4]tr-
iazole 76 ##STR00274## ##STR00275##
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(4-methoxy-naphthalen-1-yl)-5-mercapto-
-[1,2,4]triazole 77 ##STR00276## ##STR00277##
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(6-methoxy-naphthalin-1-yl)-5-mercapto-
-[1,2,4]triazole 78 ##STR00278## ##STR00279##
3-(2,4-Dihydroxy-3-chloro-5-ethyl-phenyl)-4-(naphthalen-1-yl)-5-mercapto--
[1,2,4]triazole 79 ##STR00280## ##STR00281##
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(2,3-dimethy-4-methoxy-phenyl)-5-merca-
pto-[1,2,4) triazole 80 ##STR00282## ##STR00283##
3-(2,4-Dihydroxy-phenyl)-4-(7-isopropoxy-naphthalen-1-yl)-5-mercapto-[1,2-
,4]triazole 81 ##STR00284## ##STR00285##
3-(2,4-Dihydroxy-phenyl)-4-(7-ethoxy-naphthalen-1-yl)-5-mercapto-[1,2,4]t-
riazole 82 ##STR00286## ##STR00287##
3-(2,4-Dihydroxy-phenyl)-4-(7-propoxy-naphthalen-1-yl)-5-mercapto-[1,2,4]-
triazole 83 ##STR00288## ##STR00289##
3-(2-Hydroxy-4-methoxymethyoxy-phenyl)-4-(naphthalen-1-yl)-5-mercapto-[1,-
2,4]triazole 84 ##STR00290## ##STR00291##
3-[2-Hydroxy-4-(2-hydroxy-ethoxy)-phenyl]-4-(naphthalen-1-yl)-5-mercapto--
[1,2,4]triazole 85 ##STR00292## ##STR00293##
3-(2,4-Dihydroxyphenyl)-4-(7-methoxy-naphthalen-1-yl)-5-mercapto-[1,2,4]t-
riazole 86 ##STR00294## ##STR00295##
3-(2,4-Dihydroxyphenyl)-4-(5-methoxy-naphthalen-1-yl)-5-mercapto-[1,2,4]t-
riazole 87 ##STR00296## ##STR00297##
3-(2,4-Dihydroxyphenyl)-4-(4-hydroxy-naphthalen-1-yl)-5-mercapto-[1,2,4]t-
riazole 88 ##STR00298## ##STR00299##
3-(2,4-Dihydroxyphenyl)-4-(1-isopropyl-indol-4-yl)-5-mercapto-[1,2,4]tria-
zole 89 ##STR00300## ##STR00301##
3-(2,4-Dihydroxy-5-tert-butyl-phenyl)-4-(naphthalen-1-yl)-5-mercapto-[1,2-
,4]triazole 90 ##STR00302## ##STR00303##
3-(2,4-Dihydroxy-5-propyl-phenyl)-4-(naphthalen-1-yl)-5-mercapto-[1,2,4]t-
riazole 91 ##STR00304## ##STR00305##
3-(2,4-Dihydroxy-3-methyl-5-ethyl-phenyl)-4-(naphthalen-1-yl)-5-mercapto--
[1,2,4]triazole 92 ##STR00306## ##STR00307##
3-(2,4-Dihydroxy-5-isobutyl-phenyl)-4-(naphthalen-1-yl)-5-mercapto-[1,2,4-
]triazole 93 ##STR00308## ##STR00309##
3-(2,4-Dihydroxy-phenyl)-4-(2,3-dimethoxy-phenyl)-5-mercapto-[1,2,4]triaz-
ole 94 ##STR00310## ##STR00311##
3-(2,4-Dihydroxy-phenyl)-4-(2-methoxy-3-chloro-phenyl)-5-mercapto-[1,2,4]-
triazole 95 ##STR00312## ##STR00313##
3-(2,4-Dihydroxy-phenyl)-4-(indol-4-yl)-5 -mercapto-[1,2,4]triazole
96 ##STR00314## ##STR00315##
3-(2,4-Dihydroxy-phenyl)-4-[1-(2-methoxyethoxy)-indol-4-yl]-5
-mercapto-[1,2,4]triazole 97 ##STR00316## ##STR00317##
3-(2,4-Dihydroxy-phenyl)-4-(naphthalen-1-yl)-5-hydroxy-[1,2,4]triazole
98 ##STR00318## ##STR00319##
3-(1-Oxo-3-hydroxy-pyridin-4-yl)-4-(naphthalen-1-yl)-5-mercapto-[1,2,4]tr-
iazole 99 ##STR00320## ##STR00321##
3-(2,5-Dihydroxy-4-carboxy)-4-(naphthalen-1-yl)-5-mercapto-[1,2,4]triazol-
e 100 ##STR00322## ##STR00323##
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(1-isopropyl-indol-4-yl)-5-mercapto-[1-
,2,4]triazole 101 ##STR00324## ##STR00325##
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-[1-(dimethyl-carbamoyl)-indol-4-yl]-5--
mercapto-[1,2,4]triazole 102 ##STR00326## ##STR00327##
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(1-ethyl-benzoimidazol-4-yl)-5-mercapt-
o-[1,2,4]triazole 103 ##STR00328## ##STR00329##
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(1,2,3-trimethyl-indol-5-yl)-5-mercapt-
o-[1,2,4]triazole 104 ##STR00330## ##STR00331##
3-(2,5-Dihydroxy-4-hydroxymethyl-phenyl)-4-(naphthalen-1-yl)-5-mercapto-[-
1,2,4]triazole 105 ##STR00332## ##STR00333##
3-(2-Hydroxy-4-amino-phenyl)-4-(naphthalen-1-yl)-5-mercapto-[1,2,4]triazo-
le 106 ##STR00334## ##STR00335##
3-(2-Hydroxy-4-acetylamino-phenyl)-4-(naphthalen-1-yl)-5-mercapto-[1,2,4]-
triazole 107 ##STR00336## ##STR00337##
3-(2,4-Dihydroxy-3-chloro-phenyl)-4-(naphthalen-1-yl)-5-mercapto-[1,2,4]t-
riazole 108 ##STR00338## ##STR00339##
3-(2,4-Dihydroxy-phenyl)-4-(naphthalen-1-yl)-5-mercapto-[1,2,4]triazole
109 ##STR00340## ##STR00341##
3-(2,4-Dihydroxy-phenyl)-4-(2-methyl-phenyl)-5-mercapto-[1,2,4]triazole
110 ##STR00342## ##STR00343##
3-(2,4-Dihydroxy-phenyl)-4-(2,5-dimethoxy-phenyl)-5-mercapto-[1,2,4]triaz-
ole 111 ##STR00344## ##STR00345##
3-(2,4-Dihydroxy-phenyl)-4-phenyl-5-mercapto-[1,2,4]triazole 112
##STR00346## ##STR00347##
3-(2-Hydroxy-phenyl)-4-(2-methoxy-phenyl)-5-mercapto-[1,2,4]triazole
113 ##STR00348## ##STR00349##
3-(2-Hydroxy-phenyl)-4-(4-methyl-phenyl)-5-mercapto-[1,2,4]triazole
114 ##STR00350## ##STR00351##
3-(2-Hydroxy-phenyl)-4-(4-bromo-phenyl)-5-mercapto-[1,2,4]triazole
115 ##STR00352##
3-(2,4-Dihydroxy-phenyl)-4-(naphthalen-1-yl)-5-(methyl
sulfanyl)-[1,2,4]triazole 116 ##STR00353## ##STR00354##
3-(2,4-Dimethoxy-phenyl)-4-(naphthalen-1-yl)-5-mercapto-[1,2,4]triazole
117 ##STR00355##
3-[2,4-Di-(dimethyl-carbamoyloxy)-phenyl]-4-(naphthalen-1-yl)-5-(dimethyl-
-carbamoylsulfanyl)-[1,2,4]triazole 118 ##STR00356##
3-(2,4-Dihydroxy-phenyl)-4-(naphthalen-1-yl)-5-(dimethylcarbamoylsulfanyl-
)-[1,2,4]triazole 119 ##STR00357##
3-(2,4-Diethoxycarbonyloxy-phenyl)-4-(naphthalen-1-yl)-5-(ethoxycarbonyls-
ulfanyl)-[1,2,4]triazole 120 ##STR00358##
3-(2,4-Di-isobutyryloxy-phenyl)-4-(naphthalen-1-yl)-5-(isobutyrylsulfanyl-
)-[1,2,4]triazole 121 ##STR00359##
3-[2,4-Di-(dimethyl-carbamoyloxy)-phenyl]-4-(quinolin-5-yl)-5-(dimethyl-c-
arbamoylsulfanyl)-[1,2,4]triazole 122 ##STR00360##
3-(2,4-Diacetoxy-phenyl)-4-(naphthalen-1-yl)-5-(acetylsulfanyl)-[1,2,4]tr-
iazole 123 ##STR00361## ##STR00362##
3-(2,4-Diacetoxy-phenyl)-4-(naphthalen-1-yl)-5-mercapto-[1,2,4]triazole
124 ##STR00363##
3-(2,4-Diethylcarbamoyloxy-phenyl)-4-(naphthalen-1-yl)-5-(ethylcarbamoyls-
ulfanyl)-[1,2,4]triazole 125 ##STR00364##
3-(2,4-Dihydroxy-phenyl)-4-(naphthalen-1-yl)-5-(2-hydroxyethylsulfanyl)-[-
1,2,4]triazole 126 ##STR00365## ##STR00366##
3-(2,4-Dihydroxy-phenyl)-4-ethyl-5-mercapto-[1,2,4]triazole 127
##STR00367## ##STR00368##
3-(2,4-Dihydroxy-phenyl)-4-propyl-5-mercapto-[1,2,4]triazole 128
##STR00369## ##STR00370##
3-(2,4-Dihydroxy-phenyl)-4-isopropyl-5-mercapto-[1,2,4]triazole 129
##STR00371## ##STR00372##
3-(2,4-Dihydroxy-phenyl)-4-butyl-5-mercapto-[1,2,4]triazole 130
##STR00373## ##STR00374##
3-(2,4-Dihydroxy-phenyl)-4-cyclopropyl-5-mercapto-[1,2,4]triazole
131 ##STR00375##
3-(2,4-Dihydroxy-phenyl)-4-(naphthalen-1-yl)-5-(carboxyethysulfanyl)-[1,2-
,4]triazole 132 ##STR00376## ##STR00377##
3-(2,6-Dimethoxy-5-fluoro-pyridin-3-yl)-4-(naphthalen-1-yl)-5-mercapto-[1-
,2,4]triazole 133 ##STR00378## ##STR00379##
3-(2-Methanesulfonyloxy-4-methanesulfonylamino-phenyl)-4-(naphthalen-1-yl-
)-5-mercapto-[1,2,4]triazole 134 ##STR00380## ##STR00381##
3-(2-Methoxy-phenyl)-4-(4-methoxy-phenyl)-5-mercapto-[1,2,4]triazole
135 ##STR00382## ##STR00383##
3-(3-Hydroxy-naphthalen-2-yl)-4-phenyl-5-mercapto-[1,2,4]triazole
136 ##STR00384## ##STR00385##
3-(2-Methoxy-phenyl)-4-(4-methyl-phenyl)-5-mercapto-[1,2,4]triazole
137 ##STR00386## ##STR00387##
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(3-methox-phenyl)-5-hydroxy-[1,2,4]tri-
azole 138 ##STR00388## ##STR00389##
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(naphthalen-1-yl)-5-hydroxy-[1,2,4]tri-
azole 139 ##STR00390## ##STR00391##
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(1-isopropyl-indol-3-yl)-5-hydroxy-[1,-
2,4]triazole 140 ##STR00392## ##STR00393##
2,4-Dihydroxy-5-ethyl-phenyl)-4-(1-isopropyl-indol-4-yl)-5-amino-[1,2,4]t-
riazole 141 ##STR00394## ##STR00395##
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(3-methoxy-phenyl)-5-amino-[1,2,4]tria-
zole 142 ##STR00396## ##STR00397##
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(naphthalen-1-yl)-5-amino-[1,2,4]triaz-
ole 143 ##STR00398## ##STR00399##
3-(2-Hydroxy-5-ethyloxy-phenyl)-4-(naphthalen-1-yl)-5-hydroxy-[1,2,4]tria-
zole 144 ##STR00400## ##STR00401##
3-(2-Hydroxy-5-isopropyl-phenyl)-4-(naphthalen-1-yl)-5-hydroxy-[1,2,4]tri-
azole 145 ##STR00402## ##STR00403##
3-(2-Dihydroxy-phenyl)-4-(7-fluoro-naphthalen-1-yl)-5-hydroxy-[1,2,4]tria-
zole 146 ##STR00404## ##STR00405##
3-(2,4-Dihydroxy-phenyl)-4-(2,3-difluorophenyl)-5-hydroxy-[1,2,4]triazole
147 ##STR00406## ##STR00407##
3-(2,4-Dihydroxy-phenyl)-4-[2-(1H-tetrazol-5-yl)-phenyl]-5-hydroxy-[1,2,4-
]triazole 148 ##STR00408## ##STR00409##
3-(2,4-Dihydroxy-phenyl)-4-(benzothiazol-4-yl)-5-hydroxy-[1,2,4]triazole
149 ##STR00410## ##STR00411##
3-(2,4-Dihydroxy-phenyl)-4-(9H-purin-6-yl)-5-hydroxy-[1,2,4]triazole
150 ##STR00412## ##STR00413##
3-(2,4-Dihydroxy-phenyl)-4-{4-[2-(moropholin-1-yl)-ethoxyl]-phenyl}-5-hyd-
roxy-[1,2,4]triazole 151 ##STR00414## ##STR00415##
3-(2,4-Dihydroxy-phenyl)-4-cyclopentyl-5-hydroxy-[1,2,4]triazole
152 ##STR00416##
3-(2,4-Dihydroxy-phenyl)-4-phenyl-5-(sulfamoylamino)-[1,2,4]triazole
153 ##STR00417##
3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(naphthalene-1-yl)-5-ureido-[1,2,4]t-
riazole 154 ##STR00418##
3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(2,3-difluorophenyl)-5-ureido-[1,2,4-
]triazole 155 ##STR00419##
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(1-isopropyl-indol-4-yl)-5-ureido-[1,2-
,4]triazole 156 ##STR00420##
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(quinolin-5-yl)-5-ureido-[1,2,4]triazo-
le 157 ##STR00421##
3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(naphthalene-1-yl)-5-carbamoyloxy-[1-
,2,4]triazole 158 ##STR00422##
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(3-trifluoromethyl-phenyl)-5-carbamoyl-
oxy-[1,2,4]triazole 159 ##STR00423##
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(1-methyl-indol-4-yl)-5-carbamoyloxy-[-
1,2,4]triazole 160 ##STR00424##
3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(8-methoxy-quinolin-5
-yl)-5-carbamoyloxy-[1,2,4]triazole 161 ##STR00425##
3-(2,4-Dihydroxy-5-isopropyl-phenyl)-4-(3-methyl-quinolin-5-yl)-5-carboxy-
amino-[1,2,4]triazole 162 ##STR00426##
3-(2,4-Dihydroxy-phenyl)-4-(1-methyl-2-chloro-indol-4-yl)-5-carbamoyloxy--
[1,2,4]triazole 163 ##STR00427##
3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-[3,5-di-(trifluoromethyl)-phenyl]-5--
carbamoyloxy-[1,2,4]triazole 164 ##STR00428##
3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(3-trifluoromethyl-phenyl)-5-(sulfam-
oylamino)-[1,2,4]triazole 165 ##STR00429##
3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(naphthalene-1-yl)-5-(sulfamoylamino-
)-[1,2,4]triazole 166 ##STR00430##
3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(1-isopropyl-benzoimidazol-4-yl)-5-(-
sulfamoylamino)-[1,2,4]triazole 167 ##STR00431##
3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(3-isopropylphenyl)-5-(thiocarboxyam-
ino)-[1,2,4]triazole 168 ##STR00432##
3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(3-isopropyloxy-phenyl)-5-(sulfamoyl-
oxy)-[1,2,4]triazole 169 ##STR00433##
3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(naphthalene-1-yl)-5-(sulfamoyloxy)--
[1,2,4]triazole 170 ##STR00434##
3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(1-isopropyl-benzoimidazol-4-yl)-5-(-
sulfamoyloxy)-[1,2,4]triazole 171 ##STR00435## ##STR00436##
3-(2-Hydroxy-4-ethoxycarbonyoxy-5-methoxy-phenyl)-4-(1-isopropyl-benzoimi-
dazol-4-yl)-5-hydroxy-[1,2,4]triazole 172 ##STR00437## ##STR00438##
3-(2-Hydroxy-4-ethoxycarbonyoxy-5-ethyl-phenyl)-4-(naphthalin-2-yl)-5-hyd-
roxy-[1,2,4]triazole 173 ##STR00439## ##STR00440##
3-[2-Hydroxy-4-(dimethyl-carbamoyoxy)-5-ethyl-phenyl]-4-(naphthalin-2-yl)-
-5-hydroxy-[1,2,4]triazole 174 ##STR00441## ##STR00442##
3-[2-Hydroxy-4-(dimethyl-carbamoyoxy)-5-chloro-phenyl]-4-(quinolin-5-yl)--
5-mercapto-[1,2,4]triazole 175 ##STR00443## ##STR00444##
3-[2-Hydroxy-4-(dimethyl-carbamoyoxy)-5-ethyl-phenyl]-4-(2,3-difluoro-phe-
nyl)-5-mercapto-[1,2,4]triazole 176 ##STR00445## ##STR00446##
3-[2-Hydroxy-4-isobutyryloxy-5-ethyl-phenyl]-4-(1-methyl-benzo-imidazol-4-
-yl)-5-hydroxy-[1,2,4]triazole 177 ##STR00447## ##STR00448##
3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(naphthalen-1-yl)-5-mercapto-[1,2,4]-
triazole 178 ##STR00449## ##STR00450##
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(5-hydroxy-naphthalen-1-yl)-5-mercapto-
-[1,2,4]triazole 179 ##STR00451## ##STR00452##
3-(2,4-Dihydroxy-phenyl)-4-(naphthalen-1-ylmethyl)-5-mercapto-[1,2,4]tria-
zole 180 ##STR00453## ##STR00454##
3-(2-Hydroxy-4-methoxyphenyl)-4-(naphthalen-1-yl)-5-mercapto-[1,2,4]triaz-
ole 181 ##STR00455## ##STR00456##
3-(2,4-Dihydroxy-phenyl)-4-(biphenyl-3-yl)-5-mercapto-[1,2,4]triazole
182 ##STR00457## ##STR00458##
3-(2,4-Dihydroxy-phenyl)-4-(2-methyl-5-hydroxymethyl-phenyl)-5-mercapto-[-
1,2,4]triazole 183 ##STR00459## ##STR00460##
3-(2,4-Dihydroxy-phenyl)-4-(1-dimethylcarbamoyl-indol-4-yl)-5-mercapto-[1-
,2,4]triazole 184 ##STR00461## ##STR00462##
3-(2,4,5-Trihydroxy-phenyl)-4-(naphthalene-1-yl)-5-mercapto-[1,2,4]triazo-
le 185 ##STR00463## ##STR00464##
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(2,3-dimethyl-indol-5-yl)-5-mercapto-[-
1,2,4]triazole 186 ##STR00465## ##STR00466##
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(3-t-butyl-4-methoxy-phenyl)-5-mercapt-
o-[1,2,4]triazole 187 ##STR00467## ##STR00468##
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(1-ethyl-1H-benzoimidazol-4-yl)-5-merc-
apto-[1,2,4]triazole,HCl salt 188 ##STR00469## ##STR00470##
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(1-isopropyl-7-methoxy-indol-4-yl)-5-m-
ercapto-[1,2,4]triazole 189 ##STR00471## ##STR00472##
3-(2,4-Dihydroxy-5-cyclopropyl-phenyl)-4-(naphthalene-1-yl)-5-mercapto-[1-
,2,4]triazole 190 ##STR00473## ##STR00474##
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-propyl-indol-4-yl)-5-mercapto-[1,2,-
4]triazole 191 ##STR00475## ##STR00476##
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-acetyl-2,3-dimethyl-indol-5-yl)-5-m-
ercapto-[1,2,4]triazole 192 ##STR00477## ##STR00478##
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(2-methyl-3-ethyl-benzimidazol-5-yl)-5-
-mercapto-[1,2,4]triazole 193 ##STR00479## ##STR00480##
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-ethyl-2-methyl-benzimidazol-5-yl)-5-
-mercapto-[1,2,4]triazole 194 ##STR00481## ##STR00482##
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-propyl-2,3-dimethyl-indol-5-yl)-5-m-
ercapto-[1,2,4]triazole 195 ##STR00483## ##STR00484##
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(N-methyl-tetrahydrocarbozol-7-yl)-5-m-
ercapto-[1,2,4]triazole 196 ##STR00485## ##STR00486##
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(N-methyl-cyclononan[a]indol-5-yl)-5-m-
ercapto-[1,2,4]triazole 197 ##STR00487## ##STR00488##
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-n-butyl-indol-4-yl)-5-mercapto-[1,2-
,4]triazole 198 ##STR00489## ##STR00490##
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-n-pentyl-indol-4-yl)-5-mercapto-[1,-
2,4]triazole 199 ##STR00491## ##STR00492##
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-n-hexyl-indol-4-yl)-5-mercapto-[1,2-
,4]triazole
200 ##STR00493## ##STR00494##
3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-(1-(1-methylcyclopropyl)-indol-4-
-yl)-5-mercapto-[1,2,4]triazole 201 ##STR00495## ##STR00496##
3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-(1-isopropyl-7-methoxy-indol-4-y-
l)-5-mercapto-[1,2,4]triazole 202 ##STR00497## ##STR00498##
3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-(1,2,3-trimethyl-indol-5-yl)-5-m-
ercapto-[1,2,4]triazole 203 ##STR00499##
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-isopropyl-7-methoxy-indol-4-yl)-5-m-
ercapto-[1,2,4]triazoledisodium salt 204 ##STR00500## ##STR00501##
3-(2,4-dihydroxy-5-tert-butyl-phenyl)-4-(1-isopropyl-7-methoxy-indol-4-yl-
)-5-mercapto-[1,2,4]triazole 205 ##STR00502## ##STR00503##
3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-(1-propyl-7-methoxy-indol-4-yl)--
5-mercapto-[1,2,4]triazole 206 ##STR00504## ##STR00505##
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-methyl-3-ethyl-indol-5-yl)-5-mercap-
to-[1,2,4]triazole 207 ##STR00506## ##STR00507##
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1,3-dimethyl-indol-5-yl)-5-mercapto-[-
1,2,4]triazole 208 ##STR00508## ##STR00509##
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-isopropyl-7-methoxy-indol-4-yl)-
-5-mercapto-[1,2,4]triazole 209 ##STR00510## ##STR00511##
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-methyl-3-isopropyl-indol-5-yl)-5-me-
rcapto-[1,2,4]triazole 210 ##STR00512## ##STR00513##
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(N-ethyl-carbozol-7-yl)-5-mercapto-[1,-
2,4]triazole 211 ##STR00514## ##STR00515##
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-isopropyl-7-hydroxy-indol-4-yl)-5-m-
ercapto-[1,2,4]triazole 212 ##STR00516## ##STR00517##
3-(2,4-dihydroxy.5-ethyl-phenyl)-4-(1-isopropyl-7-ethoxy-indol-4-yl)-5-me-
rcapto-[1,2,4]triazole 213 ##STR00518## ##STR00519##
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1,2-dimethyl-indol-5-yl)-5-mercapto-[-
1,2,4]triazole 214 ##STR00520## ##STR00521##
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(N-methyl-indol-5-yl)-5-mercapto-[1,2,-
4]triazole 215 ##STR00522## ##STR00523##
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(2-methyl-7-methoxy-benzofuran-4-yl)-5-
-mercapto-[1,2,4]triazole 216 ##STR00524## ##STR00525##
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(benzofuran-5-yl)-5-mercapto-[1,2,4]tr-
iazole 217 ##STR00526## ##STR00527##
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(2-methyl-1,3-benzoxaz-5-yl)-5-mercapt-
o-[1,2,4]triazole 218 ##STR00528## ##STR00529##
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1,3-dimethyl-indol-5-yl)-5-mercap-
to-[1,2,4]triazole 219 ##STR00530## ##STR00531##
3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-(1,3-dimethyl-indol-5-yl)-5-merc-
apto-[1,2,4]triazole 220 ##STR00532## ##STR00533##
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1,3-dimethyl-indol-5-yl)-5-hydroxy-[1-
,2,4]triazole 221 ##STR00534## ##STR00535##
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(N-methyl-indol-5-yl)-5-mercapto-[-
1,2,4]triazole 222 ##STR00536## ##STR00537##
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1,2-dimethyl-indol-5-yl)-5-mercap-
to-[1,2,4]triazole 223 ##STR00538## ##STR00539##
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1,3-dimethyl-indol-5-yl)-5-hydrox-
y-[1,2,4]triazole 224 ##STR00540## ##STR00541##
3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-(1-methyl-indol-5-yl)-5-mercapto-
-[1,2,4]triazole 225 ##STR00542## ##STR00543##
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1H-indol-5-yl)-5-mercapto-[1,2,4]-
triazole 226 ##STR00544## ##STR00545##
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-methyl-indol-5-yl)-5-hydroxy-[1-
,2,4]triazole 227 ##STR00546## ##STR00547##
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-ethyl-indol-5-yl)-5-mercapto-[1-
,2,4]triazole 228 ##STR00548## ##STR00549##
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-propyl-indol-5-yl)-5-mercapto-[-
1,2,4]triazole 229 ##STR00550## ##STR00551##
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-methyl-2-trifluoromethyl-benzim-
idazol-5-yl)-5-mercapto-[1,2,4]triazole 230 ##STR00552##
##STR00553##
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-methyl-indazol-5
-yl)-5-mercapto-[1,2,4]triazole 231 ##STR00554## ##STR00555##
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-methyl-indazol-6-yl)-5-mercapto-
-[1,2,4]triazole 232 ##STR00556## ##STR00557##
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-isopropyl-indol-4-yl)-5-hydroxy-
-[1,2,4]triazole 233 ##STR00558## ##STR00559##
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1,3-benzodiaxol-5-yl)-5-mercapto--
[1,2,4]triazole 234 ##STR00560## ##STR00561##
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(indan-5-yl)-5-mercapto-[1,2,4]tri-
azole 235 ##STR00562## ##STR00563##
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(2-methyl-indazol-6-yl)-5-mercapto-
-[1,2,4]triazole 236 ##STR00564## ##STR00565##
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(3-oxo-benzo[1,4]oxazin-6-yl)-5-mercap-
to-[1,2,4]triazole 237 ##STR00566## ##STR00567##
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(2-oxo-1,3-dihydro-benzoimidazol-5-yl)-
-5-mercapto-[1,2,4]triazole 238 ##STR00568## ##STR00569##
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(2H-benzo[1,4]oxazin-6-yl)-5-merca-
pto-[1,2,4]triazole 239 ##STR00570## ##STR00571##
4-Ethyl-6-[5-mercapto-4-(1-methyl-2,3-dihydro-1H-indol-5-yl)-4H-[1,2,4]tr-
iazol-3-yl]-benzene-1,3-diol 240 ##STR00572## ##STR00573##
5-(3-(5-ethyl-2,4-dihydroxyphenyl)-5-mercapto-4H-1,2,4-triazol-4-yl)indol-
in-2-one 241 ##STR00574## ##STR00575##
5-(3-(5-ethyl-2,4-dihydroxyphenyl)-5-mercapto-4H-1,2,4-triazol-4-yl)-1H-b-
enzo[d]imidazol-2(3H)-one 242 ##STR00576## ##STR00577##
5-(3-(5-ethyl-2,4-dihydroxyphenyl)-5-mercapto-4H-1,2,4-triazol-4-yl)-1-me-
thylindolin-2-one 243 ##STR00578## ##STR00579##
4-isopropyl-6-(5-mercapto-4-(4-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin--
6-yl)-4H-1,2,4-triazol-3-yl)benzene-1,3-diol 244 ##STR00580##
##STR00581##
6-(3-(5-ethyl-2,4-dihydroxyphenyl)-5-mercapto-4H-1,2,4-triazol-4-yl)-2H-b-
enzo[b][1,4]oxazin-3(4H)-one 245 ##STR00582## ##STR00583##
6-(3-(5-ethyl-2,4-dihydroxyphenyl)-5-mercapto-4H-1,2,4-triazol-4-yl)-3-me-
thylbenzo[d]thiazol-2(3H)-one 246 ##STR00584## ##STR00585##
6-(3-(5-ethyl-2,4-dihydroxyphenyl)-5-mercapto-4H-1,2,4-triazol-4-yl)benzo-
[d]thiazol-2(3H)-one
TABLE-US-00002 TABLE 2 NO. Structure Tautomeric structure Name 247
##STR00586## ##STR00587##
4-(4-(3-(diethylamino)-4-methoxyphenyl)-5-mercapto-4H-1,2,4-triazol-3-yl)-
-6-ethylbenzene-1,3-diol 248 ##STR00588## ##STR00589##
4-(4-(3-(N-isopropyl-N-propylamino)-4-methoxyphenyl)-5-mercapto-4H-1,2,4--
triazol-3-yl)-6-ethylbenzene-1,3-diol 249 ##STR00590## ##STR00591##
4-(4-(3-(N-isopropyl-N-methylamino)-4-methoxyphenyl)-5-mercapto-4H-1,2,4--
triazol-3-yl)-6-ethylbenzene-1,3-diol 250 ##STR00592## ##STR00593##
4-(4-(3-(N-ethyl-N-methylamino)-4-methoxyphenyl)-5-mercapto-4H-1,2,4-tria-
zol-3-yl)-6-ethylbenzene-1,3-diol 251 ##STR00594## ##STR00595##
4-(4-(3-(dimethylamino)-4-methoxyphenyl)-5-mercapto-4H-1,2,4-triazol-3-yl-
)-6-ethylbenzene-1,3-diol 252 ##STR00596## ##STR00597##
4-(4-(3-(dimethylamino)phenyl)-5-mercapto-4H-1,2,4-triazol-3-yl)-6-ethylb-
enzene-1,3-diol 253 ##STR00598## ##STR00599##
4-(4-(3-(N-ethyl-N-isopropylamino)-4-methoxyphenyl)-5-mercapto-4H-1,2,4-t-
riazol-3-yl)-6-ethylbenzene-1,3-diol 254 ##STR00600## ##STR00601##
4-ethyl-6-(5-mercapto-4-(3-(pyrrolidin-1-yl)phenyl)-4H-1,2,4-triazol-3-yl-
)benzene-1,3-diol 255 ##STR00602## ##STR00603##
4-ethyl-6-(5-mercapto-4-(4-methoxy-3-morpholinophenyl)-4H-1,2,4-triazol-3-
-yl)benzene-1,3-diol 256 ##STR00604## ##STR00605##
4-(4-(3-(N-isopropyl-N-propylamino)-4-methoxyphenyl)-5-mercapto-4H-1,2,4--
triazol-3-yl)-6-isopropylbenzene-1,3-diol 257 ##STR00606##
##STR00607##
4-(4-(3-(N-methyl-N-propylamino)-4-methoxyphenyl)-5-mercapto-4H-1,2,4-tri-
azol-3-yl)-6-isopropylbenzene-1,3-diol 258 ##STR00608##
##STR00609##
4-(4-(3-(N-methyl-N-ethylamino)-4-methoxy-phenyl)-5-mercapto-4H-1,2,4-tri-
azol-3-yl)-6-isopropylbenzene-1,3-diol 259 ##STR00610##
##STR00611##
4-(4-(4-(dimethylamino)-3-methoxyphenyl)-5-mercapto-4H-1,2,4-triazol-3-yl-
)-6-ethylbenzene-1,3-diol 260 ##STR00612## ##STR00613## 261
##STR00614## ##STR00615##
4-(4-(3-aminophenyl)-5-mercapto-4H-1,2,4-triazol-3-yl)-6-ethylbenzene-1,3-
-diol 262 ##STR00616## ##STR00617## 263 ##STR00618## ##STR00619##
4-(4-(3-(N-isopentyl-N-methylamino)-4-methoxyphenyl)-5-mercapto-4H-1,2,4--
triazol-3-yl)-6-isopropylbenzene-1,3-diol 264 ##STR00620##
##STR00621## 265 ##STR00622## ##STR00623##
4-(4-(3-(N-(2-(dimethylamino)ethyl)-N-methylamino)-4-methoxyphenyl)-5-mer-
capto-4H-1,2,4-triazol-3-yl)-6-isopropylbenzene-1,3-diol 266
##STR00624## ##STR00625##
4-(4-(3-(N-(2-methoxyethyl)-N-methylamino)-4-methoxyphenyl)-5-mercapto-4H-
-1,2,4-triazol-3-yl)-6-isopropylbenzene-1,3-diol 267 ##STR00626##
##STR00627##
4-(4-(3-(N-(cyclopropylmethyl)-N-methylamino)-4-methoxyphenyl)-5-mercapto-
-4H-1,2,4-triazol-3-yl)-6-isopropylbenzene-1,3-diol 268
##STR00628## ##STR00629##
4-(4-(3-(N-butyl-N-methylamino)-4-methoxyphenyl)-5-mercapto-4H-1,2,4-tria-
zol-3-yl)-6-isopropylbenzene-1,3-diol 269 ##STR00630## ##STR00631##
4-(4-(3-(N-isobutyl-N-methylamino)-4-methoxyphenyl)-5-mercapto-4H-1,2,4-t-
riazol-3-yl)-6-isopropylbenzene-1,3-diol 270 ##STR00632##
##STR00633##
4-(4-(3-(N-(2-(1H-imidazol-1-yl)ethyl)-N-methylamino)-4-methoxyphenyl)-5--
mercapto-4H-1,2,4-triazol-3-yl)-6-isopropylbenzene-1,3-diol 271
##STR00634## ##STR00635##
4-(4-(3-(N-methyl-N-propylamino)-4-methoxyphenyl)-5-mercapto-4H-1,2,4-tri-
azol-3-yl)-6-isopropylbenzene-1,3-diol 272 ##STR00636##
##STR00637##
4-(4-(3-(dimethylamino)-4-(methylthio)phenyl)-5-mercapto-4H-1,2,4-triazal-
-3-yl)-6-isopropylbenzene-1,3-diol 273 ##STR00638## ##STR00639##
4-(4-(3-(1H-pyrrol-1-yl)phenyl)-5-hydroxy-4H-1,2,4-triazol-3-yl)-6-ethylb-
enzene-1,3-diol 274 ##STR00640## ##STR00641##
4-(4-(3-(1H-imidazol-1-yl)phenyl)-5-mercapto-4H-1,2,4-triazol-3-yl)-6-iso-
propylbenzene-1,3-diol 275 ##STR00642## ##STR00643## 276
##STR00644## ##STR00645## 277 ##STR00646## ##STR00647##
4-(4-(4-(dimethylamino)phenyl)-5-mercapto-4H-1,2,4-triazol-3-yl)-6-ethylb-
enzene-1,3-diol 278 ##STR00648## ##STR00649##
4-(4-(4-(diethylamino)phenyl)-5-mercapto-4H-1,2,4-triazol-3-yl)-6-ethylbe-
nzene-1,3-diol 279 ##STR00650## ##STR00651##
4-ethyl-6-(5-mercapto-4-(4-morpholinophenyl)-4H-1,2,4-triazol-3-yl)benzen-
e-1,3-diol 280 ##STR00652## ##STR00653##
4-(4-(4-(1H-imidazol-1-yl)phenyl)-5-mercapto-4H-1,2,4-triazol-3-yl)-6-eth-
ylbenzene-1,3-diol 281 ##STR00654## ##STR00655##
4-(4-(2,5-diethoxy-4-morpholinophenyl)-5-mercapto-4H-1,2,4-triazol-3-yl)--
6-ethylbenzene-1,3-diol 282 ##STR00656## ##STR00657##
4-(4-(3-(1H-pyrrol-1-yl)phenyl)-5-mercapto-4H-1,2,4-triazol-3-yl)-6-ethyl-
benzene-1,3-diol 283 ##STR00658## ##STR00659##
4-(4-(4-(1H-pyrazol-1-yl)phenyl)-5-mercapto-4H-1,2,4-triazol-3-yl)-6-ethy-
lbenzene-1,3-diol 284 ##STR00660## ##STR00661##
4-(4-(4-(amino)-3-hydroxyphenyl)-5-mercapto-4H-1,2,4-triazol-3-yl)-6-ethy-
lbenzene-1,3-diol 285 ##STR00662## ##STR00663##
4-(4-(4-(methylamino)-3-hydroxyphenyl)-5-mercapto-4H-1,2,4-triazol-3-yl)--
6-ethylbenzene-1,3-diol 286 ##STR00664## ##STR00665##
4-(4-(4-(dimethylamino)-3-methylphenyl)-5-mercapto-4H-1,2,4-triazol-3-yl)-
-6-ethylbenzene-1,3-diol
The invention is illustrated with the following examples which are
not intended to be limiting in any way.
EXEMPLIFICATION
Example 1
##STR00666##
[0632] Preparation of
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(N-methyl-indol-5-yl)-5-hydroxy-[1-
,2,4]triazole
[0633] 2,4-dibenzyloxy-5-isopropylbenzoic acid (43.0 mmol, 1.00
equiv.) in 300 mL dichloromethane at room temperature was treated
with oxalyl chloride (47.3 mmol, 1.10 equiv.) and catalytic amount
of DMF (0.5 mL) for 1 hour. Solvent and excess oxalyl chloride were
removed on rotary evaporator. The residue was dissolved in 300 mL
dichloromethane, and treated with 1,3-dimethyl-5-aminoindole (43.0
mmol, 1.00 equiv.) and triethylamine (64.5 mmol, 1.50 equiv.) at
0.degree. C. for 1 hour. Normal aqueous workup and removal of
solvent gave a light brown solid which was washed with ether to
yield off-white solid (39.95 mmol, 93%).
[0634] Procedure 1. The off-white solid (4 mmol) of the amide
obtained above was treated with Lawesson's reagent (970 mg, 0.6
equiv.) in 40 mL toluene at 110.degree. C. for 1.5 hour. Water was
added and extracted with ethyl acetate, washed with water 2 times.
Dried, concentrated and crystallized by the combination of
sonication and addition of hexanes to give an orange solid (80%
yield)
[0635] Procedure 2. The off-white solid (4 mmol) of the amide
obtained above was treated with Lawesson's reagent (970 mg, 0.6
equiv.) in 40 mL toluene at 110.degree. C. for 1.5 hour. The
reaction was allowed to cool. Aqueous ammonium hydroxide solution
was added (2 mol equiv.) and stirred vigorously at room temperature
for 10 min. Water (200 mL) and ethyl acetate (100 mL) were added.
The organic layer was washed with water (2.times.200 mL). The
organic layer was then treated with activated carbon (10 g) and
stirred at room temperature for 1 hour. Filtration and removal of
solvent under reduced pressure gave a bright yellow solid.
[0636] The yellow solid of the thioamide obtained from either
Procedure 1 or Procedure 2 was treated with hydrazine (anhydrous,
50.0 equiv.) in ethanol at 80.degree. C. for 1.5 hour. The reaction
mixture was subjected to EtOAc/aqueous workup to remove excess
hydrazine. The organic layer was dried and filtered to remove
drying agent.
[0637] Carbonyldiimidazole (1.1 equiv.) was added to the solution,
and the solution was stirred at 35.degree. C. for 2 hours. Solvent
was pumped off, and the residue was treated with 20 mL THF and 10
mL NaOH (2M) to destroy excess carbonyldiimidazole. Normal workup
(EtOAc/aqueous) and filtration gave the desired product
5-(2,4-bis(benzyloxy)-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1,-
2,4-triazole-3-ol as light brown solid.
[0638] The solid was redissolved in THF/MeOH (1:1 100 mL) and
palladium (10 wt % on activated carbon) was added. The reaction was
stirred under a hydrogen atmosphere (50 psi) for 18 h. Filtration
through celite and removal of solvent under reduced pressure
produced the desired product (80% yield).
Example 2
##STR00667##
[0639] Preparation of
4-isopropyl-6-[4-(1-methyl-1H-indol-5-yl)-5-phenylamino-4H-[1,2,4-triazol-
-3-yl]-benzene-1,3-diol
[0640]
5-isopropyl-2,4-dimethoxy-N-1-methyl-1H-indol-5-yl)-benzamide was
prepared reacting 2,4-dimethoxy-5-isopropylbenzoic acid with
1,3-dimethyl-5-aminoindole by a procedure similar that described in
Example 1. The corresponding thioamide was prepared by reacting the
amide with Lawesson's reagent by a similar procedure as described
in Procedure 1 of Example 1. A flask was charged with the
thiobenzamide (123 mg, 0.33 mmol), dioxane (2 mL), and hydrazine
(0.5 mL). The reaction was heated to 100.degree. C. for one hour,
and the solvent was removed by evaporation to give a solid cake. To
the solid cake was added ethyl acetate (10 mL) and 10% aqueous
potassium carbonate (1 mL), and the mixture was shaken until the
solid was completely dissolved. The organic layer was isolated, and
dried with sodium sulfate. To the crude intermediate in the organic
layer was added diisopropylethylamine (86 mg, 0.66 mmol) and
phenylisocyanide dichloride (88 mg, 1.5 equivalent). The reaction
was stirred overnight, and washed with saturated aqueous ammonium
chloride, dried with sodium sulfate, and the product was purified
by column chromatography to give
[5-(5-isopropyl-2,4-dimethoxy-phenyl)-4-(1-methyl-1H-indol-5-yl)-4H-[1,2,-
4]triazol-3-yl]-phenylamine (64 mg).
[0641] A flask was charged with
[5-(5-isopropyl-2,4-dimethoxy-phenyl)-4-(1-methyl-1H-indol-5-yl)-4H-[1,2,-
4]triazol-3-yl]-phenylamine (27 mg, 0.06 mmol) and pyridium
chloride (2 g). The reactants were placed under a nitrogen
atmosphere, and the reaction was heated to 210.degree. C. for 25
minutes. To the cooled reaction mixture was added dichloromethane
and saturated ammonium chloride solution. The organic fraction was
isolated, and the product was purified by column chromatography to
give
4-isopropyl-6-[4-(1-methyl-1H-indol-5-yl)-5-phenylamino-4H-[1,2,4-triazol-
-3-yl]-benzene-1,3-diol (18 mg, 0.04 mmol). .sup.1H-NMR
(CDCl.sub.3): 7.70 (d, 1H); 7.59 (d, 1H); 7.50 (m, 3H); 7.29 (m,
2H); 7.22 (dd, 1H); 6.98 (m, 1H); 6.62 (d, 1H); 6.40 (s, 1H); 6.28
(s, 1H); 3.95 (s, 2H); 2.83 (q, 1H); 0.57 (d, 3H); 0.44 (d, 3H).
ESMS calcd (C.sub.26H.sub.25N.sub.5O.sub.2): 347.13; Found: 348.1
(M+H).sup.+.
Example 3
[0642] The compounds shown below were prepared by similar
procedures as described in Procedure 1 of Example 1. Analytical
data is provided for these compounds.
##STR00668##
[0643] ESMS calcd (C.sub.18H.sub.13N.sub.3O.sub.3): 319.1; Found:
320 (M+H).sup.+.
##STR00669##
[0644] ESMS calcd (C.sub.18H.sub.14N.sub.4O.sub.3): 318.11; Found:
319.2 (M+H).sup.+.
##STR00670##
[0645] ESMS calcd (C.sub.20H.sub.17N.sub.3O.sub.3): 347.13; Found:
348.1 (M+H).sup.+.
##STR00671##
[0646] ESMS calcd (C.sub.27H.sub.27N.sub.5O.sub.2): 453.22; Found:
454.4 (M+H).sup.+.
##STR00672##
[0647] .sup.1H-NMR (DMSO-d.sub.6): 11.85 (s, 1H); 9.61 (s, 1H);
9.43 (s, 1H); 7.30 (d, J=7.5 Hz, 2H); 7.11 (d, J=7.5 Hz, 2H); 6.76
(s, 1H); 6.26 (s, 1H); 3.50 (s, 2H); 3.00-2.90 (m, 1H); 2.47-2.42
(m, 4H); 0.98-0.93 (m, 12H).
[0648] ESMS calcd (C.sub.22H.sub.28N.sub.4O.sub.3): 453.22; Found:
454.4 (M+H).sup.+.
##STR00673##
[0649] ESMS calcd (C.sub.17H.sub.18N.sub.4O.sub.3): 326.14; Found:
327.1 (M+H).sup.+.
##STR00674##
[0650] .sup.1H-NMR (DMSO-d.sub.6): 11.90 (s, 1H); 9.59 (s, 1H);
9.44 (s, 1H); 7.18 (d, J=8.1 Hz, 1H); 7.11 (s, 1H); 6.88 (dd,
J=8.1, 1.5 Hz, 1H); 6.82 (s, 1H); 6.25 (s, 1H); 4.21-4.15 (m, 1H);
3.23 (s, 3H); 3.10-2.93 (m, 3H); 2.88-2.79 (m, 2H); 0.97 (d, J=6.9
Hz, 6H).
[0651] ESMS calcd (C.sub.21H.sub.23N.sub.3O.sub.4): 381.4; Found:
382.4 (M+H).sup.+.
##STR00675##
[0652] ESMS calcd (C.sub.19H.sub.21N.sub.3O.sub.5): 371.15; Found:
372.2 (M+H).sup.+.
##STR00676##
[0653] ESMS calcd (C.sub.22H.sub.26N.sub.4O.sub.4): 410.20; Found:
411.1 (M+H).sup.+.
##STR00677##
[0654] ESMS calcd (C.sub.19H.sub.22N.sub.4O.sub.3): 354.17; Found:
355.2 (M+H).sup.+.
##STR00678##
[0655] ESMS calcd (C.sub.20H.sub.25N.sub.5O.sub.4): 399.19; Found:
400.1 (M+H).sup.+.
##STR00679##
[0656] ESMS calcd (C.sub.20H.sub.25N.sub.5O.sub.5): 415.19; Found:
416.1 (M+H).sup.+.
##STR00680##
[0657] ESMS calcd (C.sub.23H.sub.22N.sub.4O.sub.3): 402.17; Found:
403.2 (M+H).sup.+.
##STR00681##
[0658] ESMS calcd (C.sub.23H.sub.22N.sub.4O.sub.4): 418.16; Found:
419.2 (M+H).sup.+.
##STR00682##
[0659] ESMS calcd (C.sub.21H.sub.24N.sub.4O.sub.4): 396.18; Found:
397.2 (M+H).sup.+.
##STR00683##
[0660] ESMS calcd (C.sub.23H.sub.30N.sub.4O.sub.5): 442.22; Found:
443.2 (M+H).sup.+.
##STR00684##
[0661] .sup.1H-NMR (DMSO): 12.01 (s, 1H); 9.64 (s, 1H); 9.58 (s,
1H); 7.61 (d, J=8.4 Hz, 1H); 7.52 (d, J=3.3 Hz, 1H); 7.17 (m, 1H);
6.92 (d, J=6.9, 1H); 6.23 (s, 1H); 6.19 (d, J=3.3 Hz, 1H); 4.79 (m,
1H); 2.76 (m, 1H); 1.44 (bs, 6H); 0.57 (d, J=6.9 Hz, 6H).
[0662] ESMS calcd (C.sub.23H.sub.30N.sub.4O.sub.5): 442.22; Found:
443.2 (M+H).sup.+.
##STR00685##
[0663] .sup.1H-NMR (DMSO): 11.89 (s, 1H); 9.55 (s, 1H); 9.39 (s,
1H); 6.88 (d, J=8.7 Hz, 1H); 6.77-6.79 (m, 2H); 6.50 (d, J=2.1 Hz,
1H); 6.24 (s, 1H); 3.26 (s, 3H); 2.97 (m, 1H); 2.79 (t, J=7.5 Hz,
2H); 2.48 (s, 3H); 1.30 (m, 2H); 0.96 (d, J=6.9 Hz, 6H); 0.73 (t,
J=7.5 Hz, 3H).
[0664] ESMS calcd (C.sub.22H.sub.28N.sub.4O.sub.4): 412.21; Found:
413.1 (M+H).sup.+.
##STR00686##
[0665] .sup.1H-NMR (DMSO-d.sub.6): 11.86 (s, 1H); 9.51 (s, 1H);
9.43 (s, 1H); 7.34 (d, J=6.6 Hz, 1H); 7.33 (s, 1H); 7.13 (d, J=1.8
Hz, 1H); 6.92 (dd, J=6.6 Hz, 1.8 Hz, 1H); 6.81 (s, 1H); 6.20 (s,
1H); 3.70 (s, 3H); 2.93 (hept, J=6.9 Hz, 1H); 2.15 (s, 3H); 0.88
(d, J=6.9 Hz, 6H).
[0666] ESMS calcd (C.sub.21H.sub.23N.sub.4O.sub.3): 378.17; Found:
379.1 (M+H).sup.+.
Example 4
Synthesis of the Compound of Formula (XXIVA)
Step 1: Synthesis of phenyl 1-methyl-1H-indol-5-ylcarbamate 5A
##STR00687##
[0668] To a solution of 5.62 g (35.91 mmols) of phenylchloroformate
4A in 25 mL of dichloromethane at 0.degree. C. was added, a
solution of 5.0 g (34.20 mmols) of indoleamine 3A in 25 mL of
dichloromethane drop wise (20 min) at 0.degree. C. The resultant
mixture was then stirred for 10 min at 0.degree. C. and a solution
of 6 mL (42.75 mmols) of triethylamine in mL of dichloromethane was
added drop wise (15 min) at 0.degree. C. and stirred for 5 min. To
the mixture was then added 50 mL of water and organic layer
separated. The aqueous layer was then extracted with 20 mL of
dichloromethane and organic layers combined and dried over
Na.sub.2SO.sub.4. The solution was then passed through a pad of
silica gel, eluted with additional 50 mL of 3:1 hexane:ethylacetate
and concentrated. The crude product was then crystallized with 4:1
hexane:ethylacetate to obtain 7.8 g (85.7%, 99.5% pure, I crop) and
0.78 g (8.5%, 98% pure, II crop) with a combined yield of 94%
product.
Step 2: Synthesis of N-(1-methyl-1H-indol-5-yl)hydrazinecarboxamide
6A
##STR00688##
[0670] To a stirred suspension of 35.0 g (0.131 mols) of the
carbamate 5A in 120 mL of 1,4-dioxane was added 32 mL (0.657 mols)
of hydrazine hydrate and the resultant mixture was refluxed for 3 h
and concentrated. To the crude mixture was added approx. 250 mL of
cold water and the resultant light brown precipitate was filtered
and vacuum dried. The crude solid was again treated with 150 mL of
ether and stirred for 1 h and filtered. Drying in vacuum afforded
21.6 g (80%) of 6A as grey solid.
Step 3: Synthesis of
3-(2,4-Bis-benzyloxy-5-isopropyl)benzylideneamino-1-(1-Methyl-1H-indol-'--
yl)-urea 8A
##STR00689##
[0672] To a suspension of 23.0 g (63.8 mmols) of the aldehyde 7A in
150 mL of ethanol was added 2 mL of AcOH and stirred. To the
resultant mixture was added 13.0 g (63.8 mmols) of 6A portion wise
(solid, 10 min) at room temperature and the resultant mixture was
heated at 80.degree. C. for 1 h. During this time, stirring was
difficult due to precipitate formation, therefore an additional 50
mL of ethanol was added. The mixture was cooled to RT and filtered
the precipitate, washed with 50 mL of cold ethanol and 100 mL of
ether and dried. Vacuum drying afforded 33.7 g (97%) of the product
8A as off-white solid.
[0673] ESMS calcd. for C.sub.34H.sub.34N.sub.4O.sub.3 (M+H).sup.+:
546.26; Found: 547.3
Step 4: Synthesis of
5-(2,4-Bis-benzyloxy-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-[1,-
2,4]triazol-3-ol 9A
##STR00690##
[0675] To a stirred suspension of 32.5 g (59.49 mmols) of 8A in 200
mL of ethanol was added 7.14 g (0.178 mmols) of NaOH and stirred.
To the resultant mixture, was added 39.17 g (0.118 mmols) of
K.sub.3Fe(CN).sub.6 at once and the resultant mixture was stirred
at reflux temperature (100.degree. C. oil bath external
temperature) for 8 h (till the reaction is complete, checked by
TLC). The mixture was cooled and the inorganics were filtered off.
The residues were thoroughly washed with EtOH (50 mL) and a 1:1
mixture of EtOAc:MeOH (150 mL) and filtrates were collected. The
combined filtrates were concentrated and crude mixture was
dissolved in approx 200 mL of water (still a suspension). The
mixture was then acidified with cHCl till pH 2-3 was reached. The
resultant precipitate was filtered, washed thoroughly with water
and dried. The crude product was then taken up in 90 mL of MeOH and
stirred at 50.degree. C. for 30 min and the solid obtained was
filtered washed with cold MeOH and dried to obtain 27 g of the off
white solid. From the mother liquor another 3.8 g of the grey solid
9A was isolated. Total yield=30.8 g (95%).
[0676] ESMS calcd. for C.sub.34H.sub.32N.sub.4O.sub.3 (M+H).sup.+:
544.25; Found: 545.3.
Step 5: Synthesis of
4-(5-hydroxy-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)-6-isopropy-
lbenzene-1,3-diol (XXIVA)
##STR00691##
[0678] Compound 9A (1 g, 1.84 mmol, 1.0 eq) was hydrogenated by
balloon pressure of hydrogen at room temperature in 8 mL of THF and
4 mL of methanol for 6 h. The reaction mixture was filtered through
Celite, and washed with THF and EtOAc. After removal solvents, the
reaction mixture was dissolved in 20 mL of 1 N NaOH solution, and
acidified with 1N HCl until pH is 3.about.4. The white precipitate
thus obtained was filtered, washed with water and dried using the
vacuum oven to produce off-white solid of
4-(5-hydroxy-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)-6-
-isopropylbenzene-1,3-diol 10A (0.638 g, 1.75 mmol, 95%).
[0679] .sup.1H-NMR (DMSO, 300 MHz) of (XXIVA). .delta. 11.86 (s,
1H), 9.53 (s, 1H), 9.41 (s, 1H), 9.40-9.36 (m, 3H), 6.91 (dd,
J=2.1, 9 Hz, 1H), 6.77 (s, 1H), 6.40 (d, J=3 Hz, 1H), 6.20 (s, 1H),
3.77 (s, 3H), 2.90 (hept., J=6.9 Hz, 1H), 0.87 (d, J=6.9 Hz,
6H).
[0680] ESMS calcd. for C.sub.20H.sub.20N.sub.4O.sub.3 (M+H).sup.+:
364.15; Found: 365.2
Step 5b: Synthesis of
4-(5-hydroxy-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)-6-isopropy-
lbenzene-1,3-diol (XXIVA)
##STR00692##
[0682]
5-(2,4-bis(benzyloxy)-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-
-4H-1,2,4-triazol-3-ol, (1.03 g, 1.89 mmol) was stirred with
ammonium formate (0.6 g, 9.5 mmol, 5 equiv.) in the presence of
palladium on activated carbon (100 mg, 0.1 equiv., 10 wt. %) at
55.degree. C. in reagent grade ethanol (25 ml) and water (0.5 ml)
for 1 hour. Completion was judged by TLC. The `hot` reaction
mixture was filtered through Celite and washed with hot ethanol (25
ml.times.3), and concentrated to around 1/4 volume. To this mixture
was added 100 mL of water. The white precipitate was filtered,
washed with water and dried with vacuum oven overnight to give 672
mg of
4-(5-hydroxy-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)-6-isopropy-
lbenzene-1,3-diol (97.7% yield, 99.8% HPLC purity at 232 mu).
[0683] The following table shows the results for various reaction
conditions in Step 5b.
TABLE-US-00003 Ammonium Run Compd 9A Catalyst Time Formate Yield
Purity 1 0.5 g 100 wt % 3.5 h 5 eq 96.4% 98.9% Pd/C (in 30 min,
complete reaction, judged by TLC and LC-MS) 2 1 g 10 wt % 1 h 5 eq
97.7% 99.8% Pd/C (complete reaction, judged by TLC and LC-MS) 3 1 g
24 wt % overnight 5 eq 89% 99.9% EnCat (in 1 h, complete Pd/C
reaction, judged by TLC and LC-MS) 4 10 g 10 wt % 2 h 5 eq 95.7%
99.8% Pd/C (complete reaction, judged by TLC and LC-MS)
Synthesis of Aldehyde 12A and the Compound of Formula (XXIIIA)
##STR00693##
[0685] To 70 mL of cold and stirred DMF (ice-bath) was added 31 mL
(0.328 mols, 2.5 eq. of reagent) of POCl.sub.3 drop wise over 15
min. The resultant mixture was stirred at ice-bath temperature
(0-5.degree. C.) for 30 min. To the mixture was then added 20 g
(0.13 mols) of 11A in 40 mL of anhydrous DMF drop wise at ice-bath
temperature (0-5.degree. C.) over 25 min. The resultant viscous
mixture was stirred at room temperature for 1 h and at 50.degree.
C. for 1 h.
[0686] The mixture was then poured cautiously to a cold solution of
63 g (12 eq.) of NaOH in 400 mL of water (over 10 min) with
vigorous stirring. A red colored solution was then obtained. The
mixture was then heated at 70.degree. C. for 15 min and then
cooled. It was then acidified with ice-bath cooling with cHCl till
pH2-3. The solution turned yellow-orange with same colored
precipitate formed. The mixture was stirred further (over weekend;
alternatively, anywhere between 15 min. to 1 h stirring should be
fine) and filtered. The orange colored precipitate was washed
successively with water and vacuum dried at 50.degree. C. to obtain
17.25 g (73%) of orange-light brown powder.
[0687] The compound of formula (XXIIIA) is synthesized from
compound 12A according to the following scheme:
##STR00694##
Exemplary Compounds Synthesized by the Methods of the Invention
[0688] Exemplary compounds of formula (IA') that can be synthesized
by the method II of the present invention are compounds 97,
137-173, 176, 220, and 232 depicted in Table 1 above, including
tautomers, pharmaceutically acceptable salts, solvates, clathrates,
hydrates, polymorphs or prodrugs thereof.
Example 5
Preparation of
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(N-methyl-indol-5-yl)-5-hydroxy-[1-
,2,4]triazole
##STR00695##
[0690] 2,4-dibenzyloxy-5-isopropylbenzoic acid (43.0 mmol, 1.00
equiv.) in 300 mL dichloromethane at room temperature was treated
with oxalyl chloride (47.3 mmol, 1.10 equiv.) and catalytic amount
of DMF (0.5 mL) for 1 hour. Solvent and excess oxalyl chloride were
removed on rotary evaporator. The residue was dissolved in 300 mL
dichloromethane, and treated with 1,3-dimethyl-5-aminoindole (43.0
mmol, 1.00 equiv.) and triethylamine (64.5 mmol, 1.50 equiv.) at
0.degree. C. for 1 hour. Normal aqueous workup and removal of
solvent gave a light brown solid which was washed with ether to
yield off-white solid (39.95 mmol, 93%).
[0691] Step 1. The off-white solid (4 mmol) of the amide obtained
above was treated with Lawesson's reagent (970 mg, 0.6 equiv.) in
40 mL toluene at 110.degree. C. for 1.5 hour. Water was added and
extracted with ethyl acetate, washed with water 2 times. Dried,
concentrated and crystallized by the combination of sonication and
addition of hexanes to give an orange solid (80% yield).
[0692] Step 2. The off-white solid (4 mmol) of the amide obtained
above was treated with Lawesson's reagent (970 mg, 0.6 equiv.) in
40 mL toluene at 110.degree. C. for 1.5 hour. The reaction was
allowed to cool. Aqueous ammonium hydroxide solution was added (2
mol equiv.) and stirred vigorously at room temperature for 10 min.
Water (200 mL) and ethyl acetate (100 mL) were added. The organic
layer was washed with water (2.times.200 mL). The organic layer was
then treated with activated carbon (10 g) and stirred at room
temperature for 1 hour. Filtration and removal of solvent under
reduced pressure gave a bright yellow solid.
[0693] Step 3
##STR00696##
[0694] Thioamide (3.682 g, 10.00 mmol, 1.0 equiv), methyl hydrazino
carboxylate (1.80 g, 20.0 mmol, 2.0 equiv), pyridine (2.37 mL,
around 30.0 mmol, 3.0 equiv) and 40 mL dioxane were mixed in a 100
mL round bottom flask. Mercury (II) chloride (5.43 g, 20.0 mmol,
2.0 equiv) was added to the flask, and stirred at room temperature
for half an hour. The mixture was refluxed for 4 hours. Enough
Na.sub.2S was added to the mixture after it was cooled to room
temperature and stirred for 30 minutes to quench excess mercury
chloride. Solid was removed by filtration through celite, and the
solution was subjected to EtOAc/aqueous workup. Flash
chromatography purification gave an off-white solid (3.10 g,
79%).
[0695] .sup.1H NMR (300 MHz, CDCl.sub.3), .delta. (ppm): 8.96 (br
s, 1H); 7.40 (dd, J=2.1 Hz, 0.6 Hz, 1H); 7.24-7.26 (m, 1H); 7.20
(s, 1H); 7.00-7.05 (m, 2H); 6.42 (dd, J=3.0 Hz, 0.6 Hz, 1H); 6.19
(s, 1H); 3.77 (s, 3H); 3.76 (s, 3H); 3.38 (s, 3H); 3.15 (hept,
J=7.2 Hz, 1H); 1.10 (d, J=7.2 Hz, 6H). ESMS calcd. for
C.sub.22H.sub.25N.sub.4O.sub.3 (M+H).sup.+: 392.2; Found:
392.2.
[0696] All publications, patent applications, patents, and other
documents cited herein are incorporated by reference in their
entirety. In case of conflict, the present specification, including
definitions, will control. In addition, the materials, methods, and
examples are illustrative only and not intended to be limiting.
[0697] While this invention has been particularly shown and
described with references to example embodiments thereof, it will
be understood by those skilled in the art that various changes in
form and details may be made therein without departing from the
scope of the invention encompassed by the appended claims.
* * * * *